Methods and compositions for modulating splicing

ABSTRACT

Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.

CROSS REFERENCE

This application is a continuation of International Application No.PCT/US2018/045282, filed on Aug. 3, 2018, which claims priority to U.S.Provisional Application No. 62/541,202, filed on Aug. 4, 2017; U.S.Provisional Application No. 62/562,927, filed on Sep. 25, 2017; and U.S.Provisional Application No. 62/562,948, filed on Sep. 25, 2017, each ofwhich are incorporated herein by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Apr. 3, 2020, isnamed 51503-705_301_SL.txt and is 29,813 bytes in size.

BACKGROUND

The majority of protein-coding genes in the human genome are composed ofmultiple exons (coding regions) that are separated by introns(non-coding regions). Gene expression results in a single precursormessenger RNA (pre-mRNA). The intron sequences are subsequently removedfrom the pre-mRNA by a process called splicing, which results in themature messenger RNA (mRNA). By including different combinations ofexons, alternative splicing gives rise to multiple mRNAs encodingdistinct protein isoforms. The spliceosome, an intracellular complex ofmultiple proteins and ribonucleoproteins, catalyzes splicing.

Current therapeutic approaches to direct and control mRNA expressionrequire methods such as gene therapy, genome editing, or a wide range ofoligonucleotide technologies (antisense, RNAi, etc.). Gene therapy andgenome editing act upstream of transcription of mRNA by influencing theDNA code and thereby changing mRNA expression. Oligonucleotides modulatethe action of RNA via canonical base/base hybridization. The appeal ofthis approach is in the design of the basic pharmacophore of anoligonucleotide, which can be defined in a straightforward fashion byknown base pairing to the target sequence subject. Each of thesetherapeutic modalities suffers from substantial technical, clinical, andregulatory challenges. Some limitations of oligonucleotides astherapeutics (e.g., antisense, RNAi) include unfavorablepharmacokinetics, lack of oral bioavailability, and lack ofblood-brain-barrier penetration, with the latter precluding delivery tothe brain or spinal cord after parenteral drug administration for thetreatment of diseases (e.g., neurological diseases, brain cancers). Inaddition, oligonucleotides are not taken up effectively into solidtumors without a complex delivery system such as lipid nanoparticles.Further, most of the oligonucleotides taken up into cells and tissuesremain in non-functional compartments (e.g., endosomes) and does notgain access to the cytosol and/or nucleus where the target is located.

Additionally, to anneal to a target, oligonucleotide therapies requireaccess to complementary base pairs of the target. This approach assumesthat pre-mRNA sequences exist as a linear strand of RNA in the cell.However, pre-mRNA is rarely linear; it has complex secondary andtertiary structure. Further, cis-acting elements (e.g., protein bindingelements) and trans-acting factors (e.g., splicing complex components)can create additional two-dimensional and three-dimensional complexity(e.g., by binding to the pre-mRNA). These features can be potency- andefficacy-limiting for oligonucleotide therapies.

SUMMARY

The novel small molecule splicing modulators (SMSMs) described herein donot suffer from the limitations above, nor the structural and sterichindrances that greatly limit oligonucleotide therapies (e.g., byblocking hybridization to pre-mRNA targets). Small molecules have beenessential in uncovering the mechanisms, regulations, and functions ofmany cellular processes, including DNA replication, transcription, andtranslation. While several recent reports have described screens forsmall molecule effectors of splicing, only a small number ofconstitutive or alternative splicing modulators have been identified andmany of the small-molecule inhibitors lack specificity, lackselectivity, lack potency, exhibit toxicity, or are not orallyavailable. Targeting the RNA transcriptome with small-moleculemodulators represents an untapped therapeutic approach to treat avariety of RNA-mediated diseases. Accordingly, there remains a need todevelop small-molecule RNA modulators useful as therapeutic agents.There is need in the art for novel modulators of splicing orsplicing-dependent processes. Provided herein are small moleculesplicing modulators and uses thereof that fulfill this need.

Provided herein is a compound that has the structure of Formula (IV), ora pharmaceutically acceptable salt or solvate thereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R2, —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, orfused bicyclic heteroaryl;X is —O—, —NR³—, —CR⁴R⁵—, —C(═O)—, —C(═CR² ₂)—, —S—, —S(═O)—, —S(═O)₂—,or —S(═O)(═NR¹)—;each R¹ is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,—CD₃, substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R¹)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R¹)₂, or—NR¹C(═O)R¹;R³ is —OR¹, —N(R′)₂, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl;R⁴ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; orR⁴ and R⁵ taken in combination with the carbon atom to which theyattach, form a substituted or unsubstituted C₃₋₈ cycloalkyl or asubstituted or unsubstituted C₂₋₇ heterocycloalkyl;Z is CR²; and R² is independently H, D, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl or —CH₂OR¹;W is substituted or unsubstituted C₁-C₄ alkylene, substituted orunsubstituted C₂-C₄ alkenylene, or substituted or unsubstituted C₁-C₄heteroalkylene;R is selected from the group consisting of H, a substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ fluoroalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein alkyl is optionally substituted withhydroxy, amino, substituted or unsubstituted mono-C₁₋₆ alkylamino, orsubstituted or unsubstituted di-C₁₋₆ alkylamino;R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyselected from the group consisting of H, F, OR¹, substituted orunsubstituted C₁₋₆ alkyl, a substituted or unsubstituted C₁₋₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, whereinalkyl is optionally substituted with hydroxy, amino, methoxy,substituted or unsubstituted mono-C₁₋₆ alkylamino or substituted orunsubstituted di-C₁₋₆ alkylamino;R¹¹ and R¹³, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group or a substituted or unsubstituted C₁₋₃heteroalkylene group; orR¹¹ and R¹⁵, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹³ and R¹⁴, taken in combination with the carbon atom to which theyattach, form a spirocyclic C₃₋₈ cycloalkyl; orR¹⁷ and R², taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orwhen X is —NR³—, then R³ and R² are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring; orwhen X is —NR³—, then R³ and R¹⁶ are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring;a and b are each independently selected from 0, 1, 2, or 3;c and d are each independently selected from 1, 2, 3, or 4; andwherein the compound of Formula (IV) has a stereochemical purity of atleast 80%.

In some embodiments, W is substituted or unsubstituted C₁-C₄ alkylene.

In some embodiments,

is

In some embodiments,

is

In some embodiments, X is —O—, —NR³—, —S—, —CR⁴R⁵—, —C(═O)—, or —C(═CR²₂)—.

In some embodiments, X is —O—, —NR³—, or —C(═O)—.

In some embodiments, ring Q is substituted or unsubstituted aryl.

In some embodiments, ring Q is 2-hydroxy-phenyl substituted with: 0, 1,2, or 3 substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₆alkylamino, di-C₁₋₆ alkylamino, aryl, heteroaryl, C₁₋₆ alkyl substitutedwith hydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O, and N,wherein two C₁₋₆ alkyl groups can combine with the atoms to which theyare bound to form a 5-6 membered ring; wherein heteroaryl has 5, 6, 9,or 10 ring atoms, 1, 2 or 3 ring heteroatoms selected from N, O, and S,and is substituted with 0, 1, or 2 substituents independently selectedfrom oxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆alkoxy, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁₋₆ alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl.

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

wherein each R^(B) is independently selected from cyano, halogen,hydroxy, substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₁₋₆ alkoxy, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted C_(2-s)heterocycloalkyl, heteroaryl, substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆alkyl-aryl, substituted or unsubstituted C₁₋₆ alkyl-heterocycloalkyl,substituted or unsubstituted C₁₋₆ alkyl-heteroaryl, substituted orunsubstituted C₁₋₆ alkoxy-aryl, substituted or unsubstituted C₁₋₆alkoxy-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkoxy-heteroaryl, and C₁₋₆ alkoxy substituted with hydroxy, C₁₋₆alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino; and m is 0,1, 2, or 3

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is fused bicyclic heteroaryl having 8 to 10ring atoms, 1, 2, or 3 ring heteroatoms independently selected from N, Oor S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a monocyclic heterocycle selected fromthe group consisting of:

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl

In some embodiments, X is —NR³—.

In some embodiments, R³ is —OR¹, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈cycloalkyl.

In some embodiments, R³ is C₃-C₈ cycloalkyl that is selected fromcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, R³ is cyclopropyl.

In some embodiments, R³ is C₃-C₈ cycloalkyl that is selected fromcyclopentenyl, or cyclohexenyl.

In some embodiments, R³ is —CH₃ or —CF₃.

In some embodiments, R³ is-CD₃.

In some embodiments, R³ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH or —OCH₂CH₂OCH₃.

In some embodiments, R³ is-OCD₃.

In some embodiments,

is

wherein p is 1, 2, or 3.

In some embodiments, R is H; R¹⁵ and R¹⁸ are H; and p is 2 or 3.

In some embodiments, R is H; R¹⁵ and R¹⁸ are H; and p is 2.

In some embodiments, R is H; R¹⁵ and R¹⁸ are H; and p is 3.

In some embodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 2 or 3.

In some embodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 2.

In some embodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 3.

In some embodiments,

is

wherein R¹⁹ is H, D, —CN, —OH, —OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹,—CH₂—N(R¹)₂, —S(═O)₂N(R¹)₂, —C(═O)R¹, —CO₂R¹, —C(═O)N(R¹)₂, substitutedor unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆haloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₈heterocycloalkyl.

Provided herein is a composition comprising a small molecule splicingmodulator compound (SMSM); wherein the SMSM interacts with an unpairedbulged nucleobase of an RNA duplex, and wherein the RNA duplex comprisesa splice site.

Provided herein is composition comprising a complex comprising a smallmolecule splicing modulator compound (SMSM) bound to an RNA duplex,wherein the SMSM interacts with an unpaired bulged nucleobase of an RNAduplex, and wherein the RNA duplex comprises a splice site.

In some embodiments, the duplex RNA comprises an alpha helix.

In some embodiments, the unpaired bulged nucleobase is located on anexternal portion of a helix of the duplex RNA

In some embodiments, the unpaired bulged nucleobase is located within aninternal portion of the helix of the duplex RNA.

In some embodiments, the SMSM forms one or more intermolecularinteractions with the duplex RNA.

In some embodiments, the SMSM forms one or more intermolecularinteractions with the unpaired bulged nucleobase.

In some embodiments, the intermolecular interaction is selected from thegroup comprising an ionic interaction, a hydrogen bond, a dipole-dipoleinteraction or a van der Waals interaction.

In some embodiments, a first portion of the SMSM interacts with theunpaired bulged nucleobase on a first RNA strand of the RNA duplex.

In some embodiments, a second portion of the SMSM interacts with one ormore nucleobases of a second RNA strand of the RNA duplex, wherein thefirst RNA strand is not the second RNA strand.

In some embodiments, a rate of exchange of the unpaired bulgednucleobase from within the interior of a helix of the duplex RNA to anexterior portion of the helix is reduced.

In some embodiments, the SMSM reduces a rate of rotation of the unpairedbulged nucleobase.

In some embodiments, the SMSM reduces a rate of rotation of the unpairedbulged nucleobase around a phosphate backbone of an RNA strand of theRNA duplex.

In some embodiments, the SMSM modulates a distance of the unpairedbulged nucleobase from a second nucleobase of the duplex RNA.

In some embodiments, the SMSM reduces the distance of the unpairedbulged nucleobase from a second nucleobase of the duplex RNA.

In some embodiments, the unpaired bulged nucleobase is located withinthe interior of a helix of the duplex RNA of the complex.

In some embodiments, the SMSM reduces a size of a bulge of the RNAduplex.

In some embodiments, the SMSM removes a bulge of the RNA duplex.

In some embodiments, the SMSM stabilizes a bulge of the RNA duplex.

In some embodiments, the SMSM modulates splicing at the splice site ofthe RNA duplex.

In some embodiments, the SMSM increases splicing at the splice site ofthe RNA duplex.

In some embodiments, the SMSM reduces splicing at the splice site of theRNA duplex.

In some embodiments, the unpaired bulged nucleobase has modulated basestacking within an RNA strand of the RNA duplex.

In some embodiments, the unpaired bulged nucleobase has increased basestacking within an RNA strand of the RNA duplex.

In some embodiments, the unpaired bulged nucleobase has decreased basestacking within an RNA strand of the RNA duplex.

In some embodiments, the SMSM is not an aptamer.

In some embodiments, the RNA duplex comprises pre-mRNA.

In some embodiments, the unpaired bulged nucleobase is free to rotatearound a phosphate backbone of an RNA strand of the RNA duplex in theabsence of the SMSM

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to cells, whereinthe SMSM kills the cells at an IC50 of less than 50 nM.

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to cells, whereinthe SMSM modulates splicing at a splice site sequence of a pre-mRNA thatencodes a mRNA, wherein the mRNA encodes a target protein or afunctional RNA, and wherein a total amount of the mRNA is increased atleast about 10% compared to the total amount of the mRNA encoding thetarget protein or functional RNA produced in control cells.

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to cells, whereinthe SMSM modulates splicing at a splice site sequence of a pre-mRNA thatencodes a mRNA, wherein the mRNA encodes a target protein or afunctional RNA, and wherein a total amount of the mRNA, the targetprotein and/or the functional RNA is at least 10% lower than the totalamount of the mRNA, the target protein and/or the functional RNA incontrol cells.

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to cells, whereinthe SMSM modulates splicing at a splice site sequence of a pre-mRNA thatencodes a first mRNA isoform associated with a disease or condition anda second mRNA isoform, wherein a total amount of the first mRNA isoformis decreased by at least about 10% compared to the total amount of thefirst mRNA isoform in control cells, and/or a total amount of the secondmRNA isoform is increased by at least about 10% compared to the totalamount of the first mRNA isoform in control cells.

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to cells comprisingan amount of a first mRNA isoform and an amount of a second mRNA isoformpresent in the cells; wherein a ratio of the first mRNA isoform to thesecond mRNA isoform is decreased at least 1.2 fold; wherein the firstand second mRNAs are encoded by a pre-MRNA comprising a splice sitesequence, and wherein the first mRNA isoform is associated with adisease or condition and a second mRNA isoform.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein theSMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion,intron retention, or splicing at a cryptic splice site of thepolynucleotide, and wherein the SMSM modulates splicing of the splicesite sequence.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the splice sitesequence comprises a splice site sequence selected from the groupconsisting of splice site sequences of Table 2A, Table 2B, Table 2C orTable 2D.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises a sequence selected from GGAguaag andAGAguaag.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises at least one bulged nucleotide at the −3,−2, −1, +1, +2, +3, +4, +5 or +6 position of the splice site sequence.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, wherein thesplice site sequence comprises a mutant nucleotide at the −3, −2, −1,+1, +2, +3, +4, +5 or +6 position of the splice site sequence.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the splice sitesequence comprises a sequence selected from the group consisting ofNGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U,G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is aor c; r is a or g; v is a, c or g; k is g or u.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the splice sitesequence comprises a sequence selected from the group consisting ofNNBgunnnn, NNBhunnnn, or NNBgvnnnn; wherein N or n is A, U, G or C; B isC, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is aor g; v is a, c or g; k is g or u.

In some embodiments, the splice site sequence comprises a sequenceselected from the group consisting of NNBgurrrn, NNBguwwdn, NNBguvmvn,NNBguvbbn, NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, or NNBgvdnvn;wherein N or n is A, U, G or C; B is C, G, or U; H or h is A, C, or U; dis a, g, or u; m is a or c; r is a or g; v is a, c or g; k is g or u.

In some embodiments, the nucleotide at the −3, −2, −1, +1, +2, +3, +4,+5 or +6 position of the splice site sequence is a bulged nucleotide.

In some embodiments, the nucleotide at the −3, −2, −1, +1, +2, +3, +4,+5 or +6 position of the splice site sequence is mutated nucleotide.

In some embodiments, the splice site sequence comprises a sequenceselected from the group consisting of splice site sequences of Table 2A,Table 2B, Table 2C or Table 2D.

Provided herein is a method of modulating splicing, comprisingcontacting a small molecule splicing modulator compound (SMSM) to a cellcomprising a polynucleotide with a splice site sequence, therebymodulating splicing of the polynucleotide, wherein the polynucleotide isencoded by a gene selected from the group consisting of genes of Table2A, Table 2B, Table 2C or Table 2D.

In some embodiments, the gene is SMN2.

In some embodiments, modulating splicing of the polynucleotide comprisesinhibiting skipping of exon 7.

In some embodiments, the gene is DMD.

In some embodiments, modulating splicing of the polynucleotide comprisespromoting skipping of exon 51.

Provided herein is a method of modulating splicing comprising contactinga small molecule splicing modulator compound (SMSM) to a cell; whereinthe SMSM interacts with an unpaired bulged nucleobase of an RNA duplexin the cell; wherein the duplex RNA comprises a splice site sequence;and wherein the SMSM modulates splicing of the RNA duplex.

Provided herein is a method for modulating the relative position of afirst nucleobase relative to a second nucleobase, wherein the firstnucleobase and the second nucleobase are within a duplex RNA, the methodcomprising contacting a small molecule splicing modulator compound(SMSM) to the duplex RNA, or a pharmaceutically acceptable salt thereof,wherein the first nucleobase is an unpaired bulged nucleobase of the RNAduplex; wherein the duplex RNA comprises a splice site sequence.

In some embodiments, the duplex RNA comprises a helix.

In some embodiments, the unpaired bulged nucleobase is located on anexternal portion of a helix of the duplex RNA prior to contacting theSMSM.

In some embodiments, the SMSM forms one or more intermolecularinteractions with the duplex RNA.

In some embodiments, the SMSM forms one or more intermolecularinteractions with the unpaired bulged nucleobase.

In some embodiments, the intermolecular interaction is selected from thegroup comprising an ionic interaction, a hydrogen bond, a dipole-dipoleinteraction or a van der Waals interaction.

In some embodiments, a rate of exchange of the unpaired bulgednucleobase from within the interior of a helix of the duplex RNA to anexterior portion of the helix is reduced.

In some embodiments, a rate of rotation of the unpaired bulgednucleobase is reduced.

In some embodiments, a rate of rotation of the unpaired bulgednucleobase around a phosphate backbone of an RNA strand of the RNAduplex is reduced.

In some embodiments, a distance of the unpaired bulged nucleobase from asecond nucleobase of the duplex RNA is modulated after contacting theSMSM.

In some embodiments, the distance of the unpaired bulged nucleobase froma second nucleobase of the duplex RNA is reduced.

In some embodiments, the unpaired bulged nucleobase is located withinthe interior of the helix of the duplex RNA.

In some embodiments, a size of a bulge of the RNA duplex is reduced.

In some embodiments, a bulge of the RNA duplex is removed or maintained.

In some embodiments, splicing at the splice site of the RNA duplex ispromoted.

In some embodiments, base stacking of the unpaired bulged nucleobasewithin an RNA strand of the RNA duplex is increased after contacting theSMSM.

In some embodiments, the distance of the unpaired bulged nucleobase froma second nucleobase of the duplex RNA is increased or maintained.

In some embodiments, a bulge of the RNA duplex is stabilized aftercontacting the SMSM.

In some embodiments, the unpaired bulged nucleobase is located on anexterior portion of a helix of the duplex RNA.

In some embodiments, a size of a bulge of the RNA duplex is increased.

In some embodiments, splicing at the splice site of the RNA duplex isinhibited.

In some embodiments, splicing is inhibited at the splice site

In some embodiments, base stacking of the unpaired bulged nucleobasewithin an RNA strand of the RNA duplex is reduced after contacting theSMSM.

In some embodiments, the RNA duplex comprises pre-mRNA.

Provided herein is a method of treating a subject with a tumorcomprising administering a small molecule splicing modulator compound(SMSM) to the subject, wherein a size of the tumor is reduced.

Provided herein is a method of treating a subject with a tumorcomprising administering a small molecule splicing modulator compound(SMSM) to the subject, wherein tumor growth is inhibited by at least 20.

Provided herein is a method of the treatment, prevention and/or delay ofprogression of a condition or disease comprising administering a smallmolecule splicing modulator compound (SMSM) to a subject, wherein theSMSM modulates splicing of a splice site of a polynucleotide in a cellof the subject, wherein the condition or disease is associated withsplicing of the splice site.

In some embodiments, the subject has the disease or condition.

Provided herein is a method of treating a subject with a disease orcondition comprising administering a small molecule splicing modulatorcompound (SMSM) to a subject with a disease or condition selected fromthe group consisting of diseases of Table 2A, Table 2B, Table 2C andTable 2D.

Provided herein is a method of treating a subject with a disease orcondition comprising administering a small molecule splicing modulatorcompound (SMSM) to a subject with a disease or condition, wherein theSMSM is selected from the group consisting of the SMSMs of Table 1A,Table 1B or Table 1C.

Provided herein is a method of treating a subject with a disease orcondition comprising administering a small molecule splicing modulatorcompound (SMSM) to a subject with a disease or condition, wherein theSMSM binds to a pre-mRNA comprising a splice site sequence selected fromthe group consisting of splice site sequences of Table 2A, Table 2B,Table 2C or Table 2D.

In some embodiments, the disease or condition is spinal muscularatrophy.

In some embodiments, the disease or condition is Duchenne's musculardystrophy.

In some embodiments, the SMSM is selected from the group consisting ofSMSMs of Table 1A, Table 1B and Table 1C.

In some embodiments, the SMSM is a compound described herein.

In some embodiments, the method further comprises administering anadditional therapeutic molecule to the subject.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is a human.

In some embodiments, the polynucleotide is a pre-mRNA.

In some embodiments, modulating splicing comprises preventing,inhibiting or reducing splicing at the splice site sequence of thepolynucleotide.

In some embodiments, modulating splicing comprises enhancing, promotingor increasing splicing at the splice site sequence of thepolynucleotide.

In some embodiments, the splice site sequence is a 5′ splice sitesequence, a 3′ splice site sequence, a branch point splice site sequenceor a cryptic splice site sequence.

In some embodiments, the splice site comprises a mutation, the splicesite comprises a bulge, the splice site comprises a mutation and abulge, the splice site does not comprises a mutation, the splice sitedoes not comprises a bulge, or the splice site does not comprises amutation and does not comprise a bulge.

In some embodiments, the bulge is a bulge caused by the mutation.

In some embodiments, a bulged nucleotide is a mutant nucleotide.

In some embodiments, a bulged nucleotide is not a mutant nucleotide.

In some embodiments, the SMSM decreases a KD of splicing complexcomponent to the polynucleotide.

In some embodiments, the SMSM increases a KD of splicing complexcomponent to the polynucleotide.

In some embodiments, the SMSM inhibits binding of a splicing complexcomponent to the polynucleotide at the splice site sequence, upstream ofthe splice site sequence or downstream of the splice site sequence.

In some embodiments, the SMSM promotes binding of a splicing complexcomponent to the polynucleotide at the splice site sequence, upstream ofthe splice site sequence or downstream of the splice site sequence.

In some embodiments, the polynucleotide is RNA.

In some embodiments, the RNA is a pre-mRNA.

In some embodiments, the RNA is a heterogeneous nuclear RNA.

The In some embodiments, the splice site sequence is a 5′ splice sitesequence, a 3′ splice site sequence, a branch point (BP) splice sitesequence, an exonic splicing enhancer (ESE) sequence, an exonic splicingsilencer (ESS) sequence, an intronic splicing enhancer (ISE) sequence,an intronic splicing silencer (ISS) sequence, a polypyrimidine tractsequence, or any combination thereof.

The In some embodiments, the polynucleotide is at least 5, 6, 7, 8, 9,10, 15, 20, 25, 50, 100, 250, 500, 750, 1,000, 2,000, 5,000, 10,000,50,000, 100,000, 500,000, or 1,000,000 nucleotides in length.

In some embodiments, the SMSM binds to the splice site sequence of thepolynucleotide.

In some embodiments, the SMSM interacts with a bulge of the splice sitesequence of the polynucleotide.

In some embodiments, the polynucleotide comprises a cis-acting elementsequence.

In some embodiments, the cis-acting element sequence does not comprise abulge.

In some embodiments, the cis-acting element sequence does not comprise amutation.

In some embodiments, the cis-acting element sequence comprises amutation, a bulge, or a combination thereof, at the cis-acting elementsequence, 1-1000 nucleobases upstream of the cis-acting element sequenceor 1-1000 nucleobases downstream of the cis-acting element sequence.

In some embodiments, the cis-acting element sequence comprises aregulatory element sequence that modulates recruitment of a splicingcomplex component to the polynucleotide.

In some embodiments, the cis-acting element sequence comprises aregulatory element sequence that modulates recruitment of a spliceosometo the polynucleotide.

In some embodiments, the regulatory element sequence comprises an exonicsplicing enhancer (ESE) sequence, an exonic splicing silencer (ESS)sequence, an intronic splicing enhancer (ISE) sequence, an intronicsplicing silencer (ISS) sequence, and combinations thereof.

In some embodiments, the SMSM binds to the splicing complex component.

In some embodiments, the splicing complex component is 9G8, A1 hnRNP, A2hnRNP, ASD-1, ASD-2b, ASF, B1 hnRNP, C1 hnRNP, C2hnRNP, CBP20, CBP80,CELF, F hnIRNP, FBP11, Fox-1, Fox-2, G hnRNP, H hnRNP, hnRNP 1, hnRNP 3,hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP,KH-type splicing regulatory protein (KSRP), L hnRNP, M hnRNP, mBBP,muscle-blind like (MBNL), NF45, NFAR, Nova-1, Nova-2, nPTB, P54/SFRS11,polypyrimidine tract binding protein (PTB), PRP19 complex proteins, RhnRNP, RNPC1, SAM68, SC35, SF, SFI/BBP, SF2, SF3a, SF3B, SFRS10, Smproteins, SR proteins, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38,SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR,TRA2, TRA2a/b, U hnRNP, U1 snRNP, U11 snRNP, U12 snRNP, U1-C, U2 snRNP,U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5 snRNP, U6 snRNP, Urp, YB1, orany combination thereof.

In some embodiments, the splicing complex component comprises RNA.

In some embodiments, the splicing complex component is a small nuclearRNA (snRNA).

In some embodiments, the snRNA comprises U1 snRNA, U2 snRNA, U4 snRNA,U5 snRNA, U6 snRNA, U11 snRNA, U12 snRNA, U4atac snRNA, U5 snRNA, U6atac snRNA, or any combination thereof.

In some embodiments, the splicing complex component comprises a protein.

In some embodiments, the splicing complex component comprises a smallnuclear ribonucleoprotein (snRNP).

In some embodiments, the snRNP comprises U1 snRNP, U2 snRNP, U4 snRNP,U5 snRNP, U6 snRNP, U11 snRNP, U12 snRNP, U4atac snRNP, U5 snRNP, U6atac snRNP, or any combinations thereof.

In some embodiments, the protein is a serine/arginine-rich (SR) protein.

In some embodiments, the splice site sequence comprises a base that ismismatched to a base of a snRNA sequence.

In some embodiments, a bulge is due to mismatched base pairing betweenthe splice site sequence and a snRNA sequence.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a diagram of alternative splicing of an exemplarypre-MRNA. One mRNA isoform depicted encodes a protein that enhances orpromotes cell proliferation and/or cancer. The other mRNA isoformdepicted encodes a protein that enhances or inhibits cell proliferationand/or cancer. The two isoforms differ by a single exon.

FIG. 2 depicts a diagram of an RNA (left), the RNA with a mutation(middle), and a small molecule bound to the RNA with the mutation(right). The mutation depicted disrupts a stem-loop that contains themutated base increasing 5′ss accessibility. Access to the 5′ splice sitecan is decreased by the depicted stem loop-stabilizing small moleculesplicing modulator. In this case the resulting mRNA isoform has skippedone exon by a small molecule splicing modulator.

FIG. 3 depicts diagrams of an exemplary primary RNA structure (top) (SEQID NO: 114), exemplary secondary RNA structures (middle) and exemplarytertiary RNA structures (bottom).

FIG. 4 depicts a diagram of an exemplary small molecule splicingmodulator bound to a complex comprising a polynucleotide and splicingcomplex protein.

FIG. 5 depicts a diagram of alternative splicing of exemplary pre-mRNAstranscribed from the indicated genes. mRNA isoforms depicted on the leftare normal; mRNA isoforms depicted on the right promote cancer.

FIG. 6A depicts an exemplary SMN2 pre-mRNA sequence with a bulge (SEQ IDNOs 115-116, respectively, in order of appearance).

FIG. 6B depicts an exemplary pre-mRNA sequence with a bulge (SEQ ID NOs117-118, respectively, in order of appearance).

FIG. 6C depicts an exemplary pre-mRNA sequence with a bulge (SEQ ID NOs115 and 119, respectively, in order of appearance).

FIG. 6D depicts an exemplary pre-mRNA sequence with a bulge (SEQ ID NOs115 and 120, respectively, in order of appearance).

FIG. 6E depicts an exemplary pre-mRNA sequence without a bulge (SEQ IDNOs 115 and 121, respectively, in order of appearance).

FIG. 7 depicts a graph of relative transcript levels of FOXM1 isoform A(represses cancer) and FOXM1 isoform B (promotes cancer) in A-673 cellsincubated with the indicated concentrations of an SMSM.

FIG. 8 depicts a plot of the measured IC₅₀ of cell viability of an SMSMfor the indicated cells.

FIG. 9A depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9B depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9C depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9D depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9E depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9F depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9G depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 9H depicts a graph of viable A-673 cells when incubated with theindicated concentrations of an SMSM.

FIG. 10 depicts a graph of viable A-375 cells when incubated with theindicated concentrations of an SMSM.

FIG. 11A depicts a graph of viable normal human dermal fibroblasts(NHDFs) cells when incubated with the indicated concentrations of anSMSM has a 100-fold higher therapeutic index compared to HDACinhibitors.

FIG. 11B depicts a graph of viable normal human dermal fibroblasts(NHDFs) cells when incubated with the indicated concentrations of DMSO.

FIG. 12 depicts a graph of IC₅₀ splicing vs IC₅₀ proliferation for SMSMsdisclosed herein. The results show viability potency correlates withcell splicing.

FIG. 13 illustrates representative impact of stereochemistry of depictedcompound 1 and compound 2 on cell activity.

FIG. 14A depicts a graph showing normalized fold change in A-673xenograft tumor volumes after treatment of mice with the indicated dosesof an SMSM for the indicated time.

FIG. 14B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM.

FIG. 14C depicts a graph showing normalized percent change in A-673xenograft tumor volumes post treatment of mice with the indicated dosesof an SMSM.

FIG. 15A depicts a graph showing change in A-673 xenograft tumor volumespost treatment of mice with the indicated doses of an SMSM.

FIG. 15B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM.

FIG. 16A depicts a graph showing normalized percent change in A-673xenograft tumor volumes post treatment of mice with the indicated dosesof an SMSM.

FIG. 16B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM.

FIG. 16C depicts a graph showing normalized relative transcript levelsof FOXM1 isoform B in the mice post treatment with the indicated dose ofan SMSM.

FIG. 17A depicts a graph showing normalized fold change in A-375xenograft tumor volumes post treatment of mice with the indicated dosesof an SMSM or vemurafenib.

FIG. 17B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM or vemurafenib.

FIG. 17C depicts a graph showing normalized relative transcript levelsof FOXM1 isoform B in the mice post treatment with the indicated dosesof SMSMs or vemurafenib.

FIG. 18A depicts a graph showing fold change in U87 (glioblastoma)xenograft tumor volumes three days post treatment of severe combinedimmunodeficiency (SCID) mice with the indicated doses of an SMSM.

FIG. 18B depicts a graph showing fold change in U87 (glioblastoma)xenograft tumor volumes three days post treatment of SCID mice with theindicated doses of an SMSM.

FIG. 19A depicts dorsal and ventral bioluminescence in Raji (lymphoma)xenograft SCID mice post treatment with an SMSM.

FIG. 19B depicts a graph of ventral bioluminescence in Raji (lymphoma)xenograft SCID mice post treatment with an SMSM.

FIG. 19C depicts of ventral bioluminescence in Raji (lymphoma) xenograftSCID mice five days post treatment with an SMSM.

FIG. 20A depicts a graph showing fold change in A-673 xenograft tumorvolumes post treatment with of mice with the indicated doses of an SMSM.

FIG. 20B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM.

FIG. 21A depicts a graph showing normalized percent change in A-375xenograft tumor volumes post treatment with of mice with the indicateddoses of SMSMs.

FIG. 21B depicts a graph showing volumes of tumors in A-375 xenograftmice post treatment with the indicated doses of SMSMs.

FIG. 21C depicts a graph of percent body weight change of mice posttreatment with the indicated doses of an SMSM or vemurafenib.

FIG. 22 depicts a Kaplan-Meier plot of percent survival over time ofA-673 Ewing's sarcoma mice mean after treatment with the indicated dosesof an SMSM administered twice a day (b.i.d.).

FIG. 23 depicts a graph of A-673 xenograft tumor weights post treatmentof mice with the indicated doses of SMSMs.

FIG. 24A depicts a graph showing volumes of tumors in A-375 xenograftmice post treatment with the indicated doses of vehicle, an SMSM,vehicle+radiation therapy (RT), and SMSM+radiation therapy.

FIG. 24B depicts a graph of percent body weight change of mice posttreatment with the indicated doses of vehicle, an SMSM,vehicle+radiation therapy (RT), and SMSM+radiation therapy.

DETAILED DESCRIPTION

Certain specific details of this description are set forth in order toprovide a thorough understanding of various embodiments. However, oneskilled in the art will understand that the present disclosure may bepracticed without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed disclosure.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present disclosure, suitable methods andmaterials are described below.

Definitions

The terms “compound(s) of this disclosure”, “compound(s) of the presentdisclosure”, “small molecule steric modulator(s)”, “small moleculesplicing modulator(s)” “steric modulator(s)”, “splicing modulator(s)”,“compound(s) that modify splicing” and “compound(s) modifying splicing”,“SMSM” or “small molecule that binds a target RNA,” are interchangeablyused herein and refer to compounds as disclosed herein andstereoisomers, tautomers, solvates, and salts (e.g., pharmaceuticallyacceptable salts) thereof. The terms “compound(s) of this disclosure”,“compound(s) of the present disclosure”, “small molecule stericmodulator(s)”, “small molecule splicing modulator(s)” “stericmodulator(s)”, “splicing modulator(s)”, “compound(s) that modifysplicing” and “compound(s) modifying splicing”, “SMSM” or “smallmolecule that binds a target RNA,” denote a small molecule compound thatbinds to a cell component (e.g., DNA, RNA, pre-mRNA, protein, RNP,snRNA, carbohydrates, lipids, co-factors, nutrients and/or metabolites)and modulates splicing of a target polynucleotide, e.g., a pre-mRNA. Forexample, an SMSM can bind directly or indirectly to a targetpolynucleotide, e.g., RNA (e.g., a pre-mRNA) with a mutated,non-mutated, bulged and/or aberrant splice site, resulting in modulationof splicing of the target polynucleotide. For example, an SMSM can binddirectly or indirectly to a protein, e.g., a spliceosome protein or aribonuclear protein, resulting in steric modulation of the protein andmodulation of splicing of a target RNA. For example, an SMSM can binddirectly or indirectly to a spliceosome component, e.g., a spliceosomeprotein or snRNA resulting in steric modulation of the spliceosomeprotein or snRNA and modulation of splicing of target polynucleotide.These terms specifically exclude compounds consisting ofoligonucleotides. These terms include small molecule compounds that maybind to one or more secondary or tertiary structure elements of a targetRNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel-Yjunctions, hairpins, bulge loops, pseudoknots, internal loops, and otherhigher-order RNA structural motifs.

The term “RNA” (ribonucleic acid) as used herein, meansnaturally-occurring or synthetic oligoribonucleotides independent ofsource (e.g., the RNA may be produced by a human, animal, plant, virus,or bacterium, or may be synthetic in origin), biological context (e.g.,the RNA may be in the nucleus, circulating in the blood, in vitro, celllysate, or isolated or pure form), or physical form (e.g., the RNA maybe in single-, double-, or triple-stranded form (including RNA-DNAhybrids), may include epigenetic modifications, nativepost-transcriptional modifications, artificial modifications (e.g.,obtained by chemical or in vitro modification), or other modifications,may be bound to, e.g., metal ions, small molecules, proteins such aschaperones, or co-factors, or may be in a denatured, partiallydenatured, or folded state including any native or unnatural secondaryor tertiary structure such as quadruplexes, hairpins, triplexes, threeway junctions (3WJs), four way junctions (4WJs), parallel-Y junctions,hairpins, bulge loops, pseudoknots, and internal loops, etc., and anytransient forms or structures adopted by the RNA). In some embodiments,the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In someembodiments, the RNA is 250 or more nucleotides in length. In someembodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000,4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotidesin length. In some embodiments, the RNA is between 250 and 1,000nucleotides in length. In some embodiments, the RNA is a pre-RNA,pre-miRNA, or pretranscript. In some embodiments, the RNA is anon-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), aribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA,ceRNA, pseudo-gene, viral RNA, fungal RNA, parasitic RNA, or bacterialRNA.

The term “target polynucleotide” or “target RNA,” as used herein, meansany type of polynucleotide or RNA, respectively, having a splice sitecapable of being modulated by a small molecule compound describedherein. For example, a target polynucleotide” or “target RNA,” may havea secondary or tertiary structure capable of binding a small moleculecompound described herein.

“Steric alteration”, “steric modification” or “steric modulation” hereinrefers to changes in the spatial orientation of chemical moieties withrespect to each other. A person of ordinary skill in the art wouldrecognize steric mechanisms include, but are not limited to, sterichindrance, steric shielding, steric attraction, chain crossing, stericrepulsions, steric inhibition of resonance, and steric inhibition ofprotonation.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atomin the structures herein indicates the presence of hydrogen, unlessindicated otherwise.

The definitions described herein apply irrespective of whether the termsin question appear alone or in combination. It is contemplated that thedefinitions described herein can be appended to form chemically-relevantcombinations, such as e.g. “heterocycloalkylaryl”,“haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”.The last member of the combination is the radical which is binding tothe rest of the molecule. The other members of the combination areattached to the binding radical in reversed order in respect of theliteral sequence, e.g. the combination arylalkylheterocycloalkyl refersto a heterocycloalkyl-radical which is substituted by an alkyl which issubstituted by an aryl.

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents.

The term “optional” or “optionally” denotes that a subsequentlydescribed event or circumstance can but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

The term “substituent” denotes an atom or a group of atoms replacing ahydrogen atom on the parent molecule.

The term “substituted” denotes that a specified group bears one or moresubstituents. Where any group can carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The following abbreviations are used throughout the specification:acetic acid (AcOH); ethyl acetate (EtOAc); butyl alcohol (n-BuOH);1,2-dichloroethane (DCE); dichloromethane (CH₂C₂, DCM);diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogenchloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr);N-methyl-2-pyrrolidone (NMP); methyl Iodide (Mel); n-propanol (n-PrOH);p-methoxybenzyl (PMB); triethylamine (Et₃N);[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II);(Pd(dppf)Cl₂); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc);sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP);tetrahydrofuran (THF).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

The term “oxo” refers to the ═O substituent.

The term “thioxo” refers to the ═S substituent.

The term “halo”, “halogen”, and “halide” are used interchangeably hereinand denote fluoro, chloro, bromo, or iodo.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical, having from one to twenty carbon atoms, and which is attachedto the rest of the molecule by a single bond. An alkyl comprising up to10 carbon atoms is referred to as a C₁-C₁₀ alkyl, likewise, for example,an alkyl comprising up to 6 carbon atoms is a C₁-C₆ alkyl. Alkyls (andother moieties defined herein) comprising other numbers of carbon atomsare represented similarly. Alkyl groups include, but are not limited to,C₁-C₁₀ alkyl, C₁-C₉ alkyl, C₁-C₈ alkyl, C₁-C₇ alkyl, C₁-C₆ alkyl, C₁-C₈alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈ alkyland C₄-C₈ alkyl.

Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl,n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl,1-ethyl-propyl, and the like. In some embodiments, the alkyl is methylor ethyl. In some embodiments, the alkyl is —CH(CH₃)₂ or —C(CH₃)₃.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted as described below. “Alkylene” or“alkylene chain” refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group. In someembodiments, the alkylene is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. In someembodiments, the alkylene is —CH₂—. In some embodiments, the alkylene is—CH₂CH₂—.

In some embodiments, the alkylene is —CH₂CH₂CH₂—.

The term “alkoxy” refers to a radical of the formula —OR where R is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below. Representative alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In someembodiments, the alkoxy is methoxy. In some embodiments, the alkoxy isethoxy.

The term “alkylamino” refers to a radical of the formula —NHR or —NRRwhere each R is, independently, an alkyl radical as defined above.Unless stated otherwise specifically in the specification, an alkylaminogroup may be optionally substituted as described below.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. In some embodiments, an alkenyl isselected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl,pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenylgroup include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl. In someembodiments, an alkynyl is selected from ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Non-limiting examples of an alkynylgroup include —C≡CH, —C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

The term “aromatic” refers to a planar ring having a delocalizedn-electron system containing 4n+2π electrons, where n is an integer.Aromatics can be optionally substituted. The term “aromatic” includesboth aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups(e.g., pyridinyl, quinolinyl).

The term “aryl” refers to an aromatic ring wherein each of the atomsforming the ring is a carbon atom. Aryl groups can be optionallysubstituted. Examples of aryl groups include, but are not limited tophenyl, and naphthyl. In some embodiments, the aryl is phenyl. Dependingon the structure, an aryl group can be a monoradical or a diradical(i.e., an arylene group). Unless stated otherwise specifically in thespecification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals that are optionallysubstituted. In some embodiments, an aryl group is partially reduced toform a cycloalkyl group defined herein. In some embodiments, an arylgroup is fully reduced to form a cycloalkyl group defined herein.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by same or differenthalogen atoms, particularly fluoro atoms. Examples of haloalkyl includemonofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, forexample 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes analkyl group where all hydrogen atoms of the alkyl group have beenreplaced by the same or different halogen atoms.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloalkoxyl include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxyor -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term“perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of thealkoxy group have been replaced by the same or different halogen atoms.

The term “bicyclic ring system” denotes two rings which are fused toeach other via a common single or double bond (annelated bicyclic ringsystem), via a sequence of three or more common atoms (bridged bicyclicring system) or via a common single atom (spiro bicyclic ring system).Bicyclic ring systems can be saturated, partially unsaturated,unsaturated or aromatic. Bicyclic ring systems can comprise heteroatomsselected from N, O and S.

The terms “carbocyclic” or “carbocycle” refer to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. Carbocycle includescycloalkyl and aryl.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. In some embodiments, cycloalkyls are saturatedor partially unsaturated. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls arefused with an aromatic ring (in which case the cycloalkyl is bondedthrough a non-aromatic ring carbon atom). Cycloalkyl groups includegroups having from 3 to 10 ring atoms. Representative cycloalkylsinclude, but are not limited to, cycloalkyls having from three to tencarbon atoms, from three to eight carbon atoms, from three to six carbonatoms, or from three to five carbon atoms. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, themonocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. In some embodiments, the monocyclic cycloalkyl iscyclopentenyl or cyclohexenyl. In some embodiments, the monocycliccycloalkyl is cyclopentenyl. Polycyclic radicals include, for example,adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl,decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl,norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specificallyin the specification, a cycloalkyl group may be optionally substituted.

The term “bridged” refers to any ring structure with two or more ringsthat contains a bridge connecting two bridgehead atoms. The bridgeheadatoms are defined as atoms that are the part of the skeletal frameworkof the molecule and which are bonded to three or more other skeletalatoms. In some embodiments, the bridgehead atoms are C, N, or P. In someembodiments, the bridge is a single atom or a chain of atoms thatconnects two bridgehead atoms. In some embodiments, the bridge is avalence bond that connects two bridgehead atoms. In some embodiments,the bridged ring system is cycloalkyl. In some embodiments, the bridgedring system is heterocycloalkyl.

The term “fused” refers to any ring structure described herein which isfused to an existing ring structure. When the fused ring is aheterocyclyl ring or a heteroaryl ring, any carbon atom on the existingring structure which becomes part of the fused heterocyclyl ring or thefused heteroaryl ring may be replaced with one or more N, S, and Oatoms. The non-limiting examples of fused heterocyclyl or heteroarylring structures include 6-5 fused heterocycle, 6-6 fused heterocycle,5-6 fused heterocycle, 5-5 fused heterocycle, 7-5 fused heterocycle, and5-7 fused heterocycle.

The term “haloalkyl” refers to an alkyl radical, as defined above, thatis substituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

The term “haloalkoxy” refers to an alkoxy radical, as defined above,that is substituted by one or more halo radicals, as defined above,e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy,trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy,3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like. Unless statedotherwise specifically in the specification, a haloalkoxy group may beoptionally substituted.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is aC₁-C₆ fluoroalkyl. In some embodiments, a fluoroalkyl is selected fromtrifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, or —N(aryl)-), sulfur(e.g. —S—, —S(═O)—, or —S(═O)₂—), or combinations thereof. In someembodiments, a heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In some embodiments, a heteroalkyl isattached to the rest of the molecule at a heteroatom of the heteroalkyl.In some embodiments, a heteroalkyl is a C₁-C₆ heteroalkyl.Representative heteroalkyl groups include, but are not limited to—OCH₂OMe, —OCH₂CH₂OH, —OCH₂CH₂OMe, or —OCH₂CH₂OCH₂CH₂NH₂.

The term “heteroalkylene” refers to an alkyl radical as described abovewhere one or more carbon atoms of the alkyl is replaced with a 0, N or Satom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight orbranched divalent heteroalkyl chain linking the rest of the molecule toa radical group. Unless stated otherwise specifically in thespecification, the heteroalkyl or heteroalkylene group may be optionallysubstituted as described below. Representative heteroalkylene groupsinclude, but are not limited to —OCH₂CH₂O—, —OCH₂CH₂OCH₂CH₂O—, or—OCH₂CH₂OCH₂CH₂OCH₂CH₂O—.

The term “heterocycloalkyl” refers to a cycloalkyl group that includesat least one heteroatom selected from nitrogen, oxygen, and sulfur.Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, or bicyclic ring system,which may include fused (when fused with an aryl or a heteroaryl ring,the heterocycloalkyl is bonded through a non-aromatic ring atom) orbridged ring systems. The nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized. The nitrogen atom maybe optionally quaternized. The heterocycloalkyl radical is partially orfully saturated. Examples of heterocycloalkyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes allring forms of carbohydrates, including but not limited tomonosaccharides, disaccharides and oligosaccharides. Unless otherwisenoted, heterocycloalkyls have from 2 to 12 carbons in the ring. In someembodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. Insome embodiments, heterocycloalkyls have from 2 to 10 carbons in thering and 1 or 2 N atoms. In some embodiments, heterocycloalkyls havefrom 2 to 10 carbons in the ring and 3 or 4 N atoms. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms,0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In someembodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms,0-1 O atoms, and 0-1 S atoms in the ring. It is understood that whenreferring to the number of carbon atoms in a heterocycloalkyl, thenumber of carbon atoms in the heterocycloalkyl is not the same as thetotal number of atoms (including the heteroatoms) that make up theheterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).Unless stated otherwise specifically in the specification, aheterocycloalkyl group may be optionally substituted.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) that includes at least one heteroatom selectedfrom nitrogen, oxygen and sulfur, wherein each heterocyclic group hasfrom 3 to 12 atoms in its ring system, and with the proviso that anyring does not contain two adjacent O or S atoms. In some embodiments,heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic orbridged compounds. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 12 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 12 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3 h-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The term “heteroaryl” refers to an aryl group that includes one or morering heteroatoms selected from nitrogen, oxygen and sulfur. Theheteroaryl is monocyclic or bicyclic. Illustrative examples ofmonocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl,oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran,benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline,isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline,1,8-naphthyridine, and pteridine. Illustrative examples of monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Illustrative examples of bicyclicheteroaryls include indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl,pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In someembodiments, a heteroaryl contains 0-6 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 4-6 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 Patoms, and 0-1 S atoms in the ring. In some embodiments, a heteroarylcontains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In someembodiments, heteroaryl is a C₁-C₉ heteroaryl. In some embodiments,monocyclic heteroaryl is a C₁-C₈ heteroaryl. In some embodiments,monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, a bicyclic heteroaryl is a C₆-C₉ heteroaryl.

In some embodiments, a heteroaryl group is partially reduced to form aheterocycloalkyl group defined herein.

In some embodiments, a heteroaryl group is fully reduced to form aheterocycloalkyl group defined herein.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from D, halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from D, halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄ alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄ alkyl), —S(═O)₂N(C₁-C₄ alkyl)₂,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ fluoroalkyl, C₁-C₄ heteroalkyl,C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —SC₁-C₄ alkyl, —S(═O)C₁-C₄ alkyl, and—S(═O)₂(C₁-C₄ alkyl). In some embodiments, optional substituents areindependently selected from D, halogen, —CN, —NH₂, —OH, —NH(CH₃),—N(CH₃)₂, —NH(cyclopropyl), —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. Insome embodiments, substituted groups are substituted with one or two ofthe preceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic) includes oxo (═O).

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes (p.o.),intraduodenal routes (i.d.), parenteral injection (including intravenous(i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular(i.m.), intravascular or infusion (inf.)), topical (top.) and rectal(p.r.) administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated; for example areduction and/or alleviation of one or more signs, symptoms, or causesof a disease, or any other desired alteration of a biological system.For example, an “effective amount” for therapeutic uses can be an amountof an agent that provides a clinically significant decrease in one ormore disease symptoms. An appropriate “effective” amount may bedetermined using techniques, such as a dose escalation study, inindividual cases.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in amount, potency or duration a desired effect. Forexample, in regard to enhancing splicing of a target, the term“enhancing” can refer to the ability to increase or prolong splicing,either in amount, potency or duration, of a the target.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human. The term “animal” as usedherein comprises human beings and non-human animals. In one embodiment,a “non-human animal” is a mammal, for example a rodent such as rat or amouse. In one embodiment, a non-human animal is a mouse.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

The term “preventing” or “prevention” of a disease state denotes causingthe clinical symptoms of the disease state not to develop in a subjectthat can be exposed to or predisposed to the disease state, but does notyet experience or display symptoms of the disease state.

The terms “pharmaceutical composition” and “pharmaceutical formulation”(or “formulation”) are used interchangeably and denote a mixture orsolution comprising a therapeutically effective amount of an activepharmaceutical ingredient together with one or more pharmaceuticallyacceptable excipients to be administered to a subject, e.g., a human inneed thereof.

The term “pharmaceutical combination” as used herein, means a productthat results from mixing or combining more than one active ingredientand includes both fixed and non-fixed combinations of the activeingredients. The term “fixed combination” means that the activeingredients, e.g., a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g., administration of three or more activeingredients.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use. “Pharmaceutically acceptable” can refer a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The terms “pharmaceutically acceptable excipient”, “pharmaceuticallyacceptable carrier” and “therapeutically inert excipient” can be usedinterchangeably and denote any pharmaceutically acceptable ingredient ina pharmaceutical composition having no therapeutic activity and beingnon-toxic to the subject administered, such as disintegrators, binders,fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants,surfactants, carriers, diluents, excipients, preservatives or lubricantsused in formulating pharmaceutical products.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. A “pharmaceuticallyacceptable salt” can refer to a formulation of a compound that does notcause significant irritation to an organism to which it is administeredand/or does not abrogate the biological activity and properties of thecompound. In some embodiments, pharmaceutically acceptable salts areobtained by reacting an SMSM compound of any one of Formulas (I)-(V)with an acid. Pharmaceutically acceptable salts are also obtained byreacting a compound of any one of Formulas (I)-(V) or with a base toform a salt.

The term “nucleic acid” as used herein generally refers to one or morenucleobases, nucleosides, or nucleotides, and the term includespolynucleobases, polynucleosides, and polynucleotides.

The term “polynucleotide”, as used herein generally refers to a moleculecomprising two or more linked nucleic acid subunits, e.g., nucleotides,and can be used interchangeably with “oligonucleotide”. For example, apolynucleotide may include one or more nucleotides selected fromadenosine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), orvariants thereof. A nucleotide generally includes a nucleoside and atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphate (PO₃) groups. Anucleotide can include a nucleobase, a five-carbon sugar (either riboseor deoxyribose), and one or more phosphate groups. Ribonucleotidesinclude nucleotides in which the sugar is ribose. Deoxyribonucleotidesinclude nucleotides in which the sugar is deoxyribose. A nucleotide canbe a nucleoside monophosphate, nucleoside diphosphate, nucleosidetriphosphate or a nucleoside polyphosphate. For example, a nucleotidecan be a deoxyribonucleoside polyphosphate, such as adeoxyribonucleoside triphosphate (dNTP), Exemplary dNTPs includedeoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP),deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) anddeoxythymidine triphosphate (dTTP). dNTPs can also include detectabletags, such as luminescent tags or markers (e.g., fluorophores). Forexample, a nucleotide can be a purine (i.e., A or G, or variant thereof)or a pyrimidine (i.e., C, T or U, or variant thereof). In some examples,a polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA),or derivatives or variants thereof. Exemplary polynucleotides include,but are not limited to, short interfering RNA (siRNA), a microRNA(miRNA), a plasmid DNA (pDNA), a short hairpin RNA (shRNA), smallnuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA),antisense RNA (asRNA), and heteronuclear RNA (hnRNA), and encompassesboth the nucleotide sequence and any structural embodiments thereof,such as single-stranded, double-stranded, triple-stranded, helical,hairpin, stem loop, bulge, etc. In some cases, a polynucleotide iscircular. A polynucleotide can have various lengths.

For example, a polynucleotide can have a length of at least about 7bases, 8 bases, 9 bases, 10 bases, 20 bases, 30 bases, 40 bases, 50bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobase(kb), 2 kb, 3, kb, 4 kb, 5 kb, 10 kb, 50 kb, or more. A polynucleotidecan be isolated from a cell or a tissue. For example, polynucleotidesequences may comprise isolated and purified DNA/RNA molecules,synthetic DNA/RNA molecules, and/or synthetic DNA/RNA analogs.

Polynucleotides may include one or more nucleotide variants, includingnonstandard nucleotide(s), non-natural nucleotide(s), nucleotideanalog(s) and/or modified nucleotides. Examples of modified nucleotidesinclude, but are not limited to diaminopurine, 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine,4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, 5-methyl-2-thiouracil,3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine andthe like. In some cases, nucleotides may include modifications in theirphosphate moieties, including modifications to a triphosphate moiety.Non-limiting examples of such modifications include phosphate chains ofgreater length (e.g., a phosphate chain having, 4, 5, 6, 7, 8, 9, 10 ormore phosphate moieties) and modifications with thiol moieties (e.g.,alpha-thiotriphosphate and beta-thiotriphosphates). Nucleic acidmolecules may also be modified at the base moiety (e.g., at one or moreatoms that typically are available to form a hydrogen bond with acomplementary nucleotide and/or at one or more atoms that are nottypically capable of forming a hydrogen bond with a complementarynucleotide), sugar moiety or phosphate backbone. Nucleic acid moleculesmay also contain amine-modified groups, such as amino ally 1-dUTP(aa-dUTP) and aminohexhylacrylamide-dCTP (aha-dCTP) to allow covalentattachment of amine reactive moieties, such as N-hydroxysuccinimideesters (NHS). Alternatives to standard DNA base pairs or RNA base pairsin the oligonucleotides of the present disclosure can provide higherdensity in bits per cubic mm, higher safety (resistant to accidental orpurposeful synthesis of natural toxins), easier discrimination inphoto-programmed polymerases, or lower secondary structure. Suchalternative base pairs compatible with natural and mutant polymerasesfor de novo and/or amplification synthesis are described in Betz K,Malyshev D A, Lavergne T, Welte W, Diederichs K, Dwyer T J, OrdoukhanianP, Romesberg F E, Marx A. Nat. Chem. Biol. 2012 July; 8(7):612-4, whichis herein incorporated by reference for all purposes.

As used herein, the terms “polypeptide”, “protein” and “peptide” areused interchangeably and refer to a polymer of amino acid residueslinked via peptide bonds and which may be composed of two or morepolypeptide chains. The terms “polypeptide”, “protein” and “peptide”refer to a polymer of at least two amino acid monomers joined togetherthrough amide bonds. An amino acid may be the L-optical isomer or theD-optical isomer. More specifically, the terms “polypeptide”, “protein”and “peptide” refer to a molecule composed of two or more amino acids ina specific order; for example, the order as determined by the basesequence of nucleotides in the gene or RNA coding for the protein.Proteins are essential for the structure, function, and regulation ofthe body's cells, tissues, and organs, and each protein has uniquefunctions. Examples are hormones, enzymes, antibodies, and any fragmentsthereof. In some cases, a protein can be a portion of the protein, forexample, a domain, a subdomain, or a motif of the protein. In somecases, a protein can be a variant (or mutation) of the protein, whereinone or more amino acid residues are inserted into, deleted from, and/orsubstituted into the naturally occurring (or at least a known) aminoacid sequence of the protein. A protein or a variant thereof can benaturally occurring or recombinant.

Methods for detection and/or measurement of polypeptides in biologicalmaterial are well known in the art and include, but are not limited to,Western-blotting, flow cytometry, ELISAs, RIAs, and various proteomicstechniques. An exemplary method to measure or detect a polypeptide is animmunoassay, such as an ELISA. This type of protein quantitation can bebased on an antibody capable of capturing a specific antigen, and asecond antibody capable of detecting the captured antigen. Exemplaryassays for detection and/or measurement of polypeptides are described inHarlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), ColdSpring Harbor Laboratory Press.

Methods for detection and/or measurement of RNA in biological materialare well known in the art and include, but are not limited to,Northern-blotting, RNA protection assay, RT PCR. Suitable methods aredescribed in Molecular Cloning: A Laboratory Manual (Fourth Edition) ByMichael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN978-1-936113-42-2.

As used here, a “small molecular weight compound” can be usedinterchangeably with “small molecule” or “small organic molecule”. Smallmolecules refer to compounds other than peptides or oligonucleotides;and typically have molecular weights of less than about 2000 Daltons,e.g., less than about 900 Daltons.

A ribonucleoprotein (RNP) refers to a nucleoprotein that contains RNA. ARNP can be a complex of a ribonucleic acid and an RNA-binding protein.Such a combination can also be referred to as a protein-RNA complex.These complexes can function in a number of biological functions thatinclude, but are not limited to, DNA replication, gene expression,metabolism of RNA, and pre-mRNA splicing. Examples of RNPs include theribosome, the enzyme telomerase, vault ribonucleoproteins, RNase P,heterogeneous nuclear RNPs (hnRNPs) and small nuclear RNPs (snRNPs).

Nascent RNA transcripts from protein-coding genes and mRNA processingintermediates, collectively referred to as pre-mRNA, are generally boundby proteins in the nuclei of eukaryotic cells. From the time nascenttranscripts first emerge from RNA polymerase (e.g., RNA polymerase II)until mature mRNAs are transported into the cytoplasm, the RNA moleculesare associated with an abundant set of splicing complex components(e.g., nuclear proteins and snRNAs). These proteins can be components ofhnRNPs, which can contain heterogeneous nuclear RNA (hnRNA) (e.g.,pre-mRNA and nuclear RNA complexes) of various sizes.

Splicing complex components function in splicing and/or splicingregulation. Splicing complex components can include, but are not limitedto, ribonuclear proteins (RNPs), splicing proteins, small nuclear RNAs(snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneousnuclear ribonucleoproteins (hnRNPs). Splicing complex componentsinclude, but are not limited to, those that may be required forsplicing, such as constitutive splicing, alternative splicing, regulatedsplicing and splicing of specific messages or groups of messages. Agroup of related proteins, the serine arginine rich proteins (SRproteins), can function in constitutive pre-mRNA splicing and may alsoregulate alternative splice-site selection in a concentration-dependentmanner. SR proteins typically have a modular structure that consists ofone or two RNA-recognition motifs (RRMs) and a C-terminal rich inarginine and serine residues (RS domain). Their activity in alternativesplicing may be antagonized by members of the hnRNP A/B family ofproteins. Splicing complex components can also include proteins that areassociated with one or more snRNAs. SR proteins in human include, butare not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2,SF2/ASF, 9G8, SRp75, SRp30c, SRp20 and P54/SFRS11. Other splicingcomplex components in human that can be involved in splice siteselection include, but are not limited to, U2 snRNA auxiliary factors(e.g. U2AF65, U2AF35), Urp/U2AF1-RS2, SF1/BBP, CBP80, CBP 20, SF1 andPTB/hnRNP1. hnRNP proteins in humans include, but are not limited to,A1, A2/B1, L, M, K, U, F, H, G, R, I and C1/C2. Human genes encodinghnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3,HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF,HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR,HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complexcomponents may be stably or transiently associated with a snRNP or witha transcript.

The term “intron” refers to both the DNA sequence within a gene and thecorresponding sequence in the unprocessed RNA transcript. As part of theRNA processing pathway, introns can be removed by RNA splicing eithershortly after or concurrent with transcription. Introns are found in thegenes of most organisms and many viruses. They can be located in a widerange of genes, including those that generate proteins, ribosomal RNA(rRNA), and transfer RNA (tRNA).

An “exon” can be any part of a gene that encodes a part of the finalmature RNA produced by that gene after introns have been removed by RNAsplicing. The term “exon” refers to both the DNA sequence within a geneand to the corresponding sequence in RNA transcripts.

A “spliceosome” can be assembled from snRNAs and protein complexes. Thespliceosome can remove introns from a transcribed pre-mRNA.

“Medium effective dose” (ED₅₀) is the dose at which 50% of a populationexpresses a specified response. “Medium lethal dose” (LD₅₀) is the doseat which 50% of a population dies. “Medium toxic dose” (TD₅₀) is thedose at which 50% of a population expresses a specified toxic effect.One particularly useful pharmacological indicator is the “therapeuticindex” which is traditionally defined as the ratio of LD₅₀ to ED₅₀ orthe ratio of TD₅₀ to ED₅₀. Therapeutic index provides a simple anduseful indicator of the benefit versus adverse effect of a drug. Thosedrugs which have a high therapeutic index have a large therapeuticwindow, i.e., the drugs may be administered over a wider range ofeffective doses without incurring significant adverse events.Conversely, drugs having a small therapeutic index have a smalltherapeutic window (small range of effective doses without incurringsignificant adverse events).

The term “AUC” as used herein refers to an abbreviation for “area underthe curve” in a graph of the concentration of a therapeutic agent overtime in a certain part or tissue, such as blood or plasma, of a subjectto whom the therapeutic agent has been administered.

Small Molecule Splicing Modulators (SMSMs)

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asagents for use in treating, preventing, or ameliorating a disease orcondition associated with a target RNA. The present invention providesthe unexpected discovery that certain small chemical molecules canmodify splicing events in pre-mRNA molecules, herein referred to assmall molecule splicing modulators (SMSMs). These SMSMs can modulatespecific splicing events in specific pre-mRNA molecules. These SMSMs canoperate by a variety of mechanisms to modify splicing events. Forexample, the SMSMs of this invention can: 1) interfere with theformation and/or function and/or other properties of splicing complexes,spliceosomes, and/or their components such as hnRNPs, snRNPs,SR-proteins and other splicing factors or elements, resulting in theprevention or induction of a splicing event in a pre-mRNA molecule. Asanother example; 2) prevent and/or modify post-transcriptionalregulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs,SR-proteins and other splicing factors, which can subsequently beinvolved in the formation and/or function of a spliceosome or splicingcomplex component; 3) prevent and/or modify phosphorylation,glycosylation and/or other modifications of gene products including, butnot limited to, hnRNPs, snRNPs, SR-proteins and other splicing factors,which can subsequently be involved in the formation and/or function of aspliceosome or splicing complex component; 4) bind to and/or otherwiseaffect specific pre-mRNA so that a specific splicing event is preventedor induced, e.g., via a mechanism that does not involve base pairingwith RNA in a sequence-specific manner. The small molecules of thisinvention are different from and are not related to antisense orantigene oligonucleotides.

Described herein are compounds modifying splicing of gene products foruse in the treatment, prevention and/or delay of progression of diseasesor conditions (e.g., cancer). Described herein are compounds modifyingsplicing of gene products wherein the compounds induce atranscriptionally inactive variant or transcript of a gene product.Described herein are compounds modifying splicing of gene productswherein the compounds repress a transcriptionally active variant ortranscript of a gene product.

In one aspect, described herein is a compound that has the structure ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl;X is —NR³—, —CR⁴R⁵—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR¹);each R¹ is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R¹)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R¹)₂, or—NR¹C(═O)R¹;R³ is —OR¹, —N(R¹)₂, substituted C₁-C₆ alkyl, substituted orunsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, wherein substitutedC₁-C₆ alkyl comprises one or more substituents other than —OH, —NH₂, and—CO₂H, wherein substituted or unsubstituted C₁-C₆ heteroalkyl comprisesat least 2 O atoms, 2 N atoms, or S atom, and wherein substituted C₃-C₈cycloalkyl comprises at least 1 substituent selected from D, halogen,and —OR¹;R⁴ is D, F, —CN, —OR¹, —SR¹, —N(R¹)₂, substituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;ring G is a group of the Formula

whereinZ is N or CR⁷; and R⁷ is H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl or —CH₂OR¹;a, b, and c are each independently selected from 0, 1, or 2;R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selectedfrom the group consisting of H, F, OR¹, substituted or unsubstitutedC₁₋₆ alkyl, a substituted or unsubstituted C₁₋₆ fluoroalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, wherein alkyl is optionallysubstituted with hydroxy, amino, methoxy, substituted or unsubstitutedmono-C₁₋₆ alkylamino or substituted or unsubstituted di-C₁₋₆ alkylamino;orR and R¹³, taken in combination form a fused 5 or 6 memberedheterocyclic ring having 0 or 1 additional ring heteroatoms selectedfrom N, O or S; orR¹¹ and R¹³, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹¹ and R¹⁵, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹¹ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a bond; orR¹³ and R¹⁴, taken in combination with the carbon atom to which theyattach, form a spirocyclic C₃₋₈ cycloalkyl; orR¹⁶ and R², taken in combination form a double bond; orR¹⁷ and R², taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orwhen Z is CR⁷, then R³ and R¹⁶ are optionally taken together with theintervening atoms to which they are attached form a 4, 5, or 6-memberedring; orwhen X is —NR³—, then R³ and R¹⁶ are optionally taken together with theintervening atoms to which they are attached form a 4, 5, or 6-memberedring; orwhen Z is CR⁷ and X is —CR⁴R⁵—, then R⁷ and R⁵ are optionally taken incombination form a double bond.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, ais 0, 1, or 2. In other embodiments, a is 0. In some other embodiments,a is 1. In some other embodiments, a is 2.

In some embodiments,

is

In some embodiments,

is

In some embodiments, Z is N and X is —NR³—, —CH(CH₂OR¹)—, —CH(OR¹)—,—C(═O)—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR¹)—. In some embodiments, Z isN. In some embodiments, X is —NR³—. In some embodiments, X is—CH(CH₂OR¹)—. In some embodiments, X is —CH(CH₂OH)—. In someembodiments, X is —CH(CH₂OCH₃)—. In some embodiments, X is —CH(OR¹)—. Insome embodiments, X is —CH(OH)—. In some embodiments, X is —CH(OCH₃)—.In some embodiments, X is —C(═O)—. In some embodiments, X is —S(═O)—. Insome embodiments, X is —S(═O)₂—. In some embodiments, X is—S(═O)(═NR¹)—.

In some embodiments, R³ is H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments, R³ is —OR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments, Z is CR⁷ and X is —C(═O)—, —CH(CH₂OR¹)—, or—CH(OR¹)—. In some embodiments, Z is CR⁷. In some embodiments, X is—C(═O)—. In some embodiments, X is —CH(CH₂OR¹)—. In some embodiments, Xis —CH(OR¹)—.

In some embodiments, ring Q is substituted or unsubstituted aryl. Insome embodiments, ring Q is substituted aryl. In some embodiments, ringQ is unsubstituted aryl.

In some embodiments, ring Q is substituted phenyl. In some embodiments,ring Q is 2-hydroxy-phenyl which is substituted with: 0, 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, heteroaryl, C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O and N.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith two C₁₋₆ alkyl. In some embodiments, two C₁₋₆ alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith heteroaryl. In some embodiments, heteroaryl has 5, 6, 9, or 10 ringatoms, 1, 2 or 3 ring heteroatoms selected from N, O and S, and issubstituted with 0, 1, or 2 substituents independently selected fromoxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁-6 alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith a heteroaryl selected from the group consisting of:

wherein each R^(B) is independently selected from cyano, halogen,hydroxy, substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₁₋₆ alkoxy, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted C_(2-s)heterocycloalkyl, heteroaryl, substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆alkyl-aryl, substituted or unsubstituted C₁₋₆ alkyl-heterocycloalkyl,substituted or unsubstituted C₁₋₆ alkyl-heteroaryl, substituted orunsubstituted C₁₋₆ alkoxy-aryl, substituted or unsubstituted C₁₋₆alkoxy-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkoxy-heteroaryl, and C₁₋₆ alkoxy substituted with hydroxy, C₁₋₆alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino; and m is 0,1, 2, or 3.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is a 5 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a 6 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a fused bicyclic heteroaryl having 8 to10 ring atoms, 1, 2, or 3 ring heteroatoms independently selected fromN, O or S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof:

wherein each R^(B) is independently selected from cyano, halogen,hydroxy, substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₁₋₆ alkoxy, substituted orunsubstituted C₃. cycloalkyl, substituted or unsubstituted C₂₋₈heterocycloalkyl, heteroaryl, substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆alkyl-aryl, substituted or unsubstituted C₁₋₆ alkyl-heterocycloalkyl,substituted or unsubstituted C₁₋₆ alkyl-heteroaryl, substituted orunsubstituted C₁₋₆ alkoxy-aryl, substituted or unsubstituted C₁₋₆alkoxy-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkoxy-heteroaryl, and C₁₋₆ alkoxy substituted with hydroxy, C₁₋₆alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino; and m is 1,2, or 3.

In some embodiments, X is S.

In some embodiments, X is —NR³—.

In some embodiments, R³ is —OR¹. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is —OCH₂CH₃. In some embodiments, R³ is—OCH₂CH₂CH₃. In some embodiments, R³ is —OCH(CH₃)₂.

In some embodiments, R³ is substituted C₁—C alkyl comprises one or moresubstituents other than —OH, —NH₂, and —CO₂H. In some embodiments, R³is-CD₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆ haloalkyl.In some embodiments, R³ is CF₃. In some embodiments, R³ is —CH₂CH₂F. Insome embodiments, R³ is —CH₂CH₂CH₂F. In some embodiments, R³ is —CH₂CF₃.In some embodiments, R³ is —CH₂CH₂CF₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, the substituted or unsubstituted C₁-C₆heteroalkyl comprises at least 2 O atoms or S atom. In some embodiments,R³ is —OCH₂CH₂OCH₃ or —OCH₂CH₂OCF₃. In some embodiments, R³ is—CH₂CH₂OCH₃. In some embodiments, R³ is —OCH₂CH₂OCF₃. In someembodiments, R³ is —CH₂CH₂SCH₃ or —CH₂SCH₃. In some embodiments, R³ is—CH₂CH₂SCH₃. In some embodiments, R³ is —CH₂SCH₃.

In some embodiments, R³ is substituted or unsubstituted C₃-C₈cycloalkyl. In some embodiments, R³ is substituted or unsubstitutedC₃-C₈ cycloalkyl. In some embodiments, R³ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In someembodiments, R³ is cyclopentenyl, cyclohexenyl, cycloheptenyl, orcyclooctenyl.

In some embodiments, X is —NR³— and ring G is

In some embodiments, X is —NR³— and ring G is

In some embodiments, X is —NR³— and ring G is

In some embodiments, X is —NR³— and ring G is

In some embodiments, ring G is

whereinp is 1 or 2. In some embodiments, ring G is

In some embodiments, ring G is

In some embodiments, ring G is

In some embodiments, ring G is

wherein p is 1 or 2. In some embodiments, ring G is

In some embodiments, ring G is

In some embodiments, ring G is

In some embodiments, ring G is

whereineach R^(C) is independently selected from H, D, F, —CN, —OH, —OR¹, —SR¹,—S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, —CH₂—N(R¹)₂, —NHS(═O)₂R¹, —S(═O)₂N(R¹)₂,—C(═O)R¹, —OC(═O)R¹, —CO₂R¹, —OCO₂R¹, —C(═O)N(R¹)₂, —OC(═O)N(R¹)₂,—NR¹C(═O)N(R′)₂, —NR¹C(═O)R¹, —NR¹C(═O)OR¹, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, and substituted or unsubstituted C₂-C₈ heterocycloalkyl; andq is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, ring G is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, a compound of Formula (I) is selected from acompound in Table 1A, Table 1B or Table 1C.

In one aspect, described herein is a compound that has the structure ofFormula (II), or a pharmaceutically acceptable salt or solvate thereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, orfused bicyclic heteroaryl;X is —O—, —NR³—, —CR⁴R⁵—, —C(═O)—, —C(═C(R²)₂)—, —S—, —S(═O)—, —S(═O)₂—,or —S(═O)(═NR¹)—; ring S is fused bicyclic heterocycle;R is selected from the group consisting of H, a substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ fluoroalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein alkyl is optionally substituted withhydroxy, amino, substituted or unsubstituted mono-C₁₋₆ alkylamino, orsubstituted or unsubstituted di-C₁₋₆ alkylamino; each R¹ isindependently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R¹)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R)₂, or—NR¹C(═O)R¹;R³ is H, —OR¹, —N(R¹)₂, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁴ is H, D, F, —CN, —OR¹, —SR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; orR⁴ and R⁵ taken in combination with the carbon atom to which theyattach, form a substituted or unsubstituted C₃₋₈ cycloalkyl or asubstituted or unsubstituted C₂₋₇ heterocycloalkyl; and wherein thecompound of Formula (II) has a stereochemical purity of at least 80%.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, ais 0, 1, or 2. In other embodiments, a is 0. In some other embodiments,a is 1. In some other embodiments, a is 2.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, X is —O—, —NR³—, —S—, —CR⁴R⁵—, —C(═O)—, or —C(═CR²₂)—. In some embodiments, X is —O—. In some embodiments, X is —NR³—. Insome embodiments, X is-S—. In some embodiments, X is —CR⁴R⁵—. In someembodiments, X is —C(═O)—. In some embodiments, X is —C(═CR² ₂)—.

In some embodiments, X is —CH(CH₂OR¹)— or —CH(OR¹)—. In someembodiments, X is —CH(CH₂OR¹)—.

In some embodiments, X is —CH(OR¹)—.

In some embodiments, R³ is H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments, R³ is —OR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments, ring Q is substituted or unsubstituted monocyclicaryl. In some embodiments, ring Q is substituted monocyclic aryl. Insome embodiments, ring Q is unsubstituted monocyclic aryl.

In some embodiments, ring Q is substituted phenyl. In some embodiments,ring Q is 2-hydroxy-phenyl which is substituted with: 0, 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, heteroaryl, C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O and N.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith two C₁₋₆ alkyl. In some embodiments, two C₁₋₆ alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith heteroaryl. In some embodiments, heteroaryl has 5, 6, 9, or 10 ringatoms, 1, 2 or 3 ring heteroatoms selected from N, O and S, and issubstituted with 0, 1, or 2 substituents independently selected fromoxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁₋₆ alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl. In some embodiments, ring Q is

wherein ring P is heteroaryl In some embodiments, the heteroaryl isselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₁₋₆ alkoxy,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted C_(2-s) heterocycloalkyl, heteroaryl, substituted orunsubstituted heterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstitutedC₁₋₆ alkyl-aryl, substituted or unsubstituted C₁₋₆alkyl-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is a 5 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a 6 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a fused bicyclic heteroaryl having 8 to10 ring atoms, 1, 2, or 3 ring heteroatoms independently selected fromN, O or S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃. cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 1, 2, or 3.

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, X is —NR³—.

In some embodiments, R³ is —OR¹. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is —OCH₂CH₃. In some embodiments, R³ is—OCH₂CH₂CH₃. In some embodiments, R³ is —OCH(CH₃)₂.

In some embodiments, R³ is-CD₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆ haloalkyl.In some embodiments, R³ is CF₃. In some embodiments, R³ is —CH₂CH₂F. Insome embodiments, R³ is —CH₂CH₂CH₂F. In some embodiments, R³ is —CH₂CF₃.In some embodiments, R³ is —CH₂CH₂CF₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R³ is —OCH₂CH₂OCH₃ or —OCH₂CH₂OCF₃. Insome embodiments, R³ is —CH₂CH₂OCH₃.

In some embodiments, R³ is substituted or unsubstituted C₃-C₈cycloalkyl. In some embodiments, R³ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

In some embodiments, R³ is cyclopentenyl, cyclohexenyl, cycloheptenyl,or cyclooctenyl.

In some embodiments,

is

wherein Z is CR⁷, and R⁷ is H, D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, or —CH₂OR¹.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

wherein Z is CR⁷, and R⁷ is H, D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, or —CH₂OR¹.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

wherein ring R is substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, the compound of Formula (II) is not racemic. Insome preferred embodiments, the compound of Formula (II) issubstantially free of other isomers. In some preferred embodiments, thecompound of Formula (V) is a single isomer substantially free of otherisomers. In some preferred embodiments, the compound of Formula (II)comprises 25% or less of other isomers. In some preferred embodiments,the compound of Formula (II) comprises 20% or less of other isomers. Insome preferred embodiments, the compound of Formula (II) comprises 15%or less of other isomers. In some preferred embodiments, the compound ofFormula (II) comprises 10% or less of other isomers. In some preferredembodiments, the compound of Formula (II) comprises 5% or less of otherisomers. In some preferred embodiments, the compound of Formula (II)comprises 1% or less of other isomers.

In some preferred embodiments, the compound of Formula (II) has astereochemical purity of at least 75%. In some preferred embodiments,the compound of Formula (II) has a stereochemical purity of at least80%. In some preferred embodiments, the compound of Formula (II) has astereochemical purity of at least 85%. In some preferred embodiments,the compound of Formula (II) has a stereochemical purity of at least90%. In some preferred embodiments, the compound of Formula (II) has astereochemical purity of at least 95%. In some preferred embodiments,the compound of Formula (II) has a stereochemical purity of at least96%. In some preferred embodiments, the compound of Formula (II) has astereochemical purity of at least 97%. In some preferred embodiments,the compound of Formula (II) has a stereochemical purity of at least98%. In some preferred embodiments, the compound of Formula (II) has astereochemical purity of at least 99%.

In some preferred embodiments, the asymmetric carbon atom (CR⁷) of thecompound of Formula (I) is present in enantiomerically enriched form. Incertain embodiments, the asymmetric carbon atom (CR⁷) of the compound ofFormula (II) has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (S)- or(R)-configuration.

In some embodiments, a compound of Formula (II) is selected from acompound in Table 1A, Table 1B or Table 1C.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, described herein is a compound that has the structure ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R¹)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is substituted or unsubstituted monocyclic aryl, substituted orunsubstituted bicyclic aryl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted fused bicyclic heteroaryl;X is —NR³—, —CR⁴R⁵—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or—S(═O)(═NR¹)—;each R¹ is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R¹)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R¹)₂, or—NR¹C(═O)R¹;R³ is —OR¹, —N(R¹)₂, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁴ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;Z is N or CR⁷; and R⁷ is H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl or —CH₂OR¹; a, b, and c areeach independently selected from 0, 1, or 2;R¹¹, R¹², R¹³, and R¹⁴ are each independently selected from the groupconsisting of H, F, OR¹, substituted or unsubstituted C₁₋₆ alkyl, asubstituted or unsubstituted C₁₋₆ fluoroalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, wherein alkyl is optionally substitutedwith hydroxy, amino, methoxy, substituted or unsubstituted mono-C₁₋₆alkylamino or substituted or unsubstituted di-C₁₋₆ alkylamino;R¹⁵, R¹⁶, and R¹⁷ are each independently selected from H, F, OR¹, andsubstituted or unsubstituted C₁₋₆ alkyl; orR¹¹ and R¹³, taken in combination form a bond or substituted orunsubstituted C₁₋₃ alkylene group; orR¹¹ and R¹⁵, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹¹ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a bond or substituted orunsubstituted C₁₋₃ alkylene group; orR¹³ and R¹⁴, taken in combination with the carbon atom to which theyattach, form a spirocyclic C₃₋₈ cycloalkyl; orwhen Z is CR⁷, then R¹⁶ and R⁷, are optionally taken together with theintervening atoms to which they are attached to form a double bond or asubstituted or unsubstituted C₁₋₃ alkylene group; orwhen Z is CR⁷ and X is NR³, then R³ and R⁷ are optionally taken togetherwith the intervening atoms to which they are attached to form asubstituted or unsubstituted C₁₋₃ alkylene group; orwhen Z is CR⁷ and X is NR³, then R³ and R¹⁶ are optionally takentogether with the intervening atoms to which they are attached to form asubstituted or unsubstituted C₁₋₃ alkylene group; orwhen Z is CR⁷ and X is —CR⁴R⁵—, then R⁷ and R⁵ are optionally taken incombination to form a double bond; andY is W-L-V, whereinW is —C(═O)—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR¹)—, —C(═O)O—, —C(═O)NR¹—,—S(═O)NR¹—, or —S(═O)₂NR′—; L is absent, substituted or unsubstitutedC₁-C₄alkylene, substituted or unsubstituted C₂-C₄alkenylene, substitutedor unsubstituted C₂-C₄alkynylene, substituted or unsubstituted C₁-C₄heteroalkylene, substituted or unsubstituted C₁-C₄cycloalkylene,substituted or unsubstituted C₁-C₄ heterocycloalkylene, substituted orunsubstituted arylene, or substituted or unsubstituted monocyclicheteroarylene, or a combination thereof; andV is —CN, —OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R′)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄ fluoroalkyl, substitutedor unsubstituted C₁-C₄ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedmonocyclic heteroaryl.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, ais 0, 1, or 2. In other embodiments, a is 0. In some other embodiments,a is 1. In some other embodiments, a is 2.

In some other embodiments,

is

In some other embodiments,

is

In some other embodiments,

is

In some other embodiments,

is

In some other embodiments,

is

In some embodiments, Z is N. In some embodiments, Z is CR⁷.

In some embodiments, X is —O—, —NR³—, —S—, —CR⁴R⁵—, —C(═O)—,—C(═C(R²)₂)—, —S(═O)—, —S(═O)₂—, or —S(═O)(═NR¹)—. In some embodiments,X is-O—. In some embodiments, X is —NR³—. In some embodiments, X is —S—.In some embodiments, X is —CR⁴R⁵—. In some embodiments, X is —C(═O)—. Insome embodiments, X is —C(═C(R²)₂)—. In some embodiments, X is —S(═O)—.In some embodiments, X is —S(═O)₂—. In some embodiments, X is—S(═O)(═NR¹)—.

In some embodiments, X is —CH(CH₂OR¹)— or —CH(OR¹)—. In someembodiments, X is —CH(CH₂OR¹)—. In some embodiments, X is —CH(OR¹)—.

In some embodiments, R³ is H, —OR¹, —N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments, R³ is —OR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments, ring Q is substituted or unsubstituted monocyclicaryl. In some embodiments, ring Q is substituted monocyclic aryl. Insome embodiments, ring Q is unsubstituted monocyclic aryl.

In some embodiments, ring Q is substituted phenyl. In some embodiments,ring Q is 2-hydroxy-phenyl which is substituted with: 0, 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, heteroaryl, C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O and N.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith two C₁₋₆ alkyl. In some embodiments, two C₁₋₆ alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith heteroaryl. In some embodiments, heteroaryl has 5, 6, 9, or 10 ringatoms, 1, 2 or 3 ring heteroatoms selected from N, O and S, and issubstituted with 0, 1, or 2 substituents independently selected fromoxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁₋₆ alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl. In some embodiments, ring Q is

wherein ring P is heteroaryl.

In some embodiments, ring Q is

wherein ring P is heteroaryl, wherein the heteroaryl is selected fromthe group consisting of:

wherein each R^(B) is independently selected from cyano, halogen,hydroxy, substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, OCD₃,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₁₋₆ alkoxy, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈heterocycloalkyl, heteroaryl, substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆alkyl-aryl, substituted or unsubstituted C₁₋₆ alkyl-heterocycloalkyl,substituted or unsubstituted C₁₋₆ alkyl-heteroaryl, substituted orunsubstituted C₁₋₆ alkoxy-aryl, substituted or unsubstituted C₁₋₆alkoxy-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkoxy-heteroaryl, and C₁₋₆ alkoxy substituted with hydroxy, C₁₋₆alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino; and m is 0,1, 2, or 3.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is a 5 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁-6 alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a 6 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a fused bicyclic heteroaryl having 8 to10 ring atoms, 1, 2, or 3 ring heteroatoms independently selected fromN, O or S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 1, 2, or 3.

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, Z is CR⁷ and X is —NR³—, —CR⁴R⁵—, —C(═O)—, —S—, or—O—. In some embodiments, Z is CR⁷ and X is —NR³—. In some embodiments,Z is CR⁷ and X is —CR⁴R⁵—. In some embodiments, Z is CR⁷ and X is—C(═O)—. In some embodiments, Z is CR⁷ and X is —S—. In someembodiments, Z is CR⁷ and X is —O—.

In some embodiments, Z is CR⁷ and X is —NR³—.

In some embodiments, each R⁷ is independently H, D, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,or —CH₂OR¹.

In some embodiments, R³ is —OR¹, substituted or unsubstituted C₁-C₆haloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, orsubstituted or unsubstituted C₃-C₈ cycloalkyl. In some embodiments, R³is —OR¹. In some embodiments, R³ is substituted or unsubstituted C₁-C₆haloalkyl. In some embodiments, R³ is substituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R³ is substituted or unsubstitutedC₃-C₈ cycloalkyl. In some embodiments, R³ is-CD₃.

In some embodiments, R³ is cyclopropyl. In some embodiments, R³ iscyclobutyl. In some embodiments, R³ is cyclopentyl. In some embodiments,R³ is cyclohexyl. In some embodiments, R³ is cycloheptyl. In someembodiments, R³ is cyclooctyl.

In some embodiments, R³ is cyclopentenyl. In some embodiments, R³ iscyclohexenyl. In some embodiments, R³ is cycloheptenyl. In someembodiments, R³ is cyclooctenyl.

In some embodiments, R³ is —CF₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂CH₂F. Insome embodiments, R³ is —CF₃. In some embodiments, R³ is —CH₂CH₂F. Insome embodiments, R³ is —CH₂CF₃. In some embodiments, R³ is —CH₂CH₂CH₂F.

In some embodiments, R³ is —OCH₃. In some embodiments, R³ is —OCH₂CH₃.In some embodiments, R³ is —OCH₂CH₂OH. In some embodiments, R³ is—CH₂CH₂OCH₃. In some embodiments, R³ is —OCH₂CH₂OCH₃.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, p is 1 or 2. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments,

is

whereineach R^(C) is independently selected from D, F, —CN, —OH, —OR¹, —SR¹,—S(═O)R¹, —S(═O)₂R¹, —N(R′)₂, —CH₂—N(R′)₂, —NHS(═O)₂R¹, —S(═O)₂N(R′)₂,—C(═O)R¹, —OC(═O)R¹, —CO₂R¹, —OCO₂R¹, —C(═O)N(R′)₂, —OC(═O)N(R′)₂,—NR¹C(═O)N(R′)₂, —NR¹C(═O)R¹, —NR¹C(═O)OR¹, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, and substituted or unsubstituted C₂-C₈ heterocycloalkyl; andq is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, Y is —C(═O)(CH₂)_(y)NH₂, —S(═O)(CH₂)_(y)NH₂, or—S(═O)₂(CH₂)_(y)NH₂, wherein y is 0, 1, or 2. In some embodiments, Y is—C(═O)NH₂. In some embodiments, Y is —C(═O)CH₂NH₂. In some embodiments,Y is —C(═O)CH₂CH₂NH₂. In some embodiments, Y is —S(═O)NH₂. In someembodiments, Y is —S(═O)CH₂NH₂. In some embodiments, Y is—S(═O)CH₂CH₂NH₂. In some embodiments, Y is —S(═O)₂NH₂. In someembodiments, Y is —S(═O)₂CH₂NH₂. In some embodiments, Y is—S(═O)₂CH₂CH₂NH₂.

In some embodiments, Y is —C(═O)(CH₂)_(y)CH═CH₂ or —C(═O)(CH₂)_(y)C≡CH,wherein y is 0, 1, or 2. In some embodiments, Y is —C(═O)CH═CH₂. In someembodiments, Y is —C(═O)CH₂CH═CH₂. In some embodiments, Y is—C(═O)CH₂CH₂CH═CH₂. In some embodiments, Y is —C(═O)CH—CH₂. In someembodiments, Y is —C(═O)CH₂CH—CH₂. In some embodiments, Y is—C(═O)CH₂CH₂CH—CH₂.

In some embodiments, Y is

or

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

wherein y is 0, 1, or 2.

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

wherein y is 0, 1, or 2.

In some embodiments, In some embodiments, Y is

In some embodiments, In some embodiments, Y is or

In some embodiments, Y is

In some embodiments, a compound of Formula (III) is selected from acompound in Table 1A, Table 1B or Table 1C.

In one aspect, described herein is a compound that has the structure ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R′, —N(R′)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R′)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R′)₂, —OC(═O)N(R′)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, orfused bicyclic heteroaryl;X is —O—, —NR³—, —CR⁴R⁵—, —C(═O)—, —C(═CR² ₂)—, —S—, —S(═O)—, —S(═O)₂—,or —S(═O)(═NR¹)—;each R¹ is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R¹)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R¹)₂, or—NR¹C(═O)R¹;R³ is H, —OR¹, —N(R¹)₂, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁴ is H, D, F, —CN, —OR¹, —SR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; orR⁴ and R⁵ taken in combination with the carbon atom to which theyattach, form a substituted or unsubstituted C₃s cycloalkyl or asubstituted or unsubstituted C₂₋₇ heterocycloalkyl;Z is CR⁷; and R⁷ is H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl or —CH₂OR¹;W is substituted or unsubstituted C₁-C₄alkylene, substituted orunsubstituted C₂-C₄alkenylene, or substituted or unsubstituted C₁-C₄heteroalkylene;R is selected from the group consisting of H, a substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ fluoroalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein alkyl is optionally substituted withhydroxy, amino, substituted or unsubstituted mono-C₁₋₆ alkylamino, orsubstituted or unsubstituted di-C₁₋₆ alkylamino;R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyselected from the group consisting of H, F, OR¹, substituted orunsubstituted C₁₋₆ alkyl, a substituted or unsubstituted C₁₋₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, whereinalkyl is optionally substituted with hydroxy, amino, methoxy,substituted or unsubstituted mono-C₁₋₆ alkylamino or substituted orunsubstituted di-C₁₋₆ alkylamino;R¹¹ and R¹³, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group or a substituted or unsubstituted C₁₋₃heteroalkylene group; orR¹¹ and R¹⁵, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹³ and R¹⁴, taken in combination with the carbon atom to which theyattach, form a spirocyclic C₃₋₈ cycloalkyl; or R¹⁷ and R², taken incombination form a substituted or unsubstituted C₁₋₃ alkylene group; orwhen X is —NR³—, then R³ and R² are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring; orwhen X is —NR³—, then R³ and R¹⁶ are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring;a and b are each independently selected from 0, 1, 2, or 3;c and d are each independently selected from 1, 2, 3, or 4; andwherein the compound of Formula (IV) has a stereochemical purity of atleast 80%.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, ais 0, 1, or 2. In other embodiments, a is 0. In some other embodiments,a is 1. In some other embodiments, a is 2.

In some embodiments, W is substituted or unsubstituted C₁-C₄ alkylene.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, X is —O—, —NR³—, —S—, —CR⁴R⁵—, —C(═O)—, or —C(═CR²₂)—. In some embodiments, X is —O—, —NR³—, or —C(═O)—. In someembodiments, X is —O—. In some embodiments, X is —NR³—. In someembodiments, X is —S—. In some embodiments, X is —CR⁴R⁵—. In someembodiments, X is —C(═O)—. In some embodiments, X is —C(═CR² ₂)—.

In some embodiments, X is —CH(CH₂OR¹)— or —CH(OR¹)—. In someembodiments, X is —CH(CH₂OR¹)—.

In some embodiments, X is —CH(OR¹)—.

In some embodiments, R³ is H, —OR¹, —N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments, R³ is —OR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments, ring Q is substituted or unsubstituted monocyclicaryl. In some embodiments, ring Q is substituted monocyclic aryl. Insome embodiments, ring Q is unsubstituted monocyclic aryl.

In some embodiments, ring Q is substituted phenyl. In some embodiments,ring Q is 2-hydroxy-phenyl which is substituted with: 0, 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, heteroaryl, C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O and N.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith two C₁₋₆ alkyl. In some embodiments, two C₁₋₆ alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith heteroaryl. In some embodiments, heteroaryl has 5, 6, 9, or 10 ringatoms, 1, 2 or 3 ring heteroatoms selected from N, O and S, and issubstituted with 0, 1, or 2 substituents independently selected fromoxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁₋₆ alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl. In some embodiments, ring Q is

wherein ring P is heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl. In some embodiments, ring Q is

wherein ring P is heteroaryl. In some embodiments, ring P is heteroaryland the heteroaryl is selected from the group consisting of:

wherein

each R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring P is heteroaryl selected from the groupconsisting of:

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is a 5 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a 6 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a fused bicyclic heteroaryl having 8 to10 ring atoms, 1, 2, or 3 ring heteroatoms independently selected fromN, O or S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof:

wherein each R^(B) is independently selected from cyano, halogen,hydroxy, substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₁₋₆ alkoxy, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₈heterocycloalkyl, heteroaryl, substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆alkyl-aryl, substituted or unsubstituted C₁₋₆ alkyl-heterocycloalkyl,substituted or unsubstituted C₁₋₆ alkyl-heteroaryl, substituted orunsubstituted C₁₋₆ alkoxy-aryl, substituted or unsubstituted C₁₋₆alkoxy-heterocycloalkyl, substituted or unsubstituted C₁₋₆alkoxy-heteroaryl, and C₁₋₆ alkoxy substituted with hydroxy, C₁₋₆alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino; and m is 1,2, or 3.

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, X is —NR³—.

In some embodiments, R³ is —OR¹, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈cycloalkyl.

In some embodiments, R³ is —OR¹. In some embodiments, R³ is —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH or —OCH₂CH₂OCH₃. In some embodiments, R³ is —OCH₃.In some embodiments, R³ is —OCH₂CH₃. In some embodiments, R³ is—OCH₂CH₂CH₃. In some embodiments, R³ is —OCH(CH₃)₂. In some embodiments,R³ is —OCD₃.

In some embodiments, R³ is-CD₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆ haloalkyl.In some embodiments, R³ is CF₃. In some embodiments, R³ is —CH₂CH₂F. Insome embodiments, R³ is —CH₂CH₂CH₂F. In some embodiments, R³ is —CH₂CF₃.In some embodiments, R³ is —CH₂CH₂CF₃.

In some embodiments, R³ is-CH₃ or —CF₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R³ is —OCH₂CH₂OCH₃ or —OCH₂CH₂OCF₃. Insome embodiments, R³ is —CH₂CH₂OCH₃.

In some embodiments, R³ is substituted or unsubstituted C₃-C₈cycloalkyl. In some embodiments, R³ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In someembodiments, R³ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In some embodiments, R³ is cyclopropyl. In some embodiments, R³ iscyclobutyl. In some embodiments, R³ is cyclopentyl. In some embodiments,R³ is cyclohexyl.

In some embodiments, R³ is cyclopentenyl, cyclohexenyl, cycloheptenyl,or cyclooctenyl. In some embodiments, R³ is cyclopentenyl orcyclohexenyl. In some embodiments, R³ is cyclopentenyl. In someembodiments, R³ is cyclohexenyl.

In some embodiments,

is

wherein p is 1, 2, or 3.

In some embodiments,

is

wherein p is 1, 2, or 3. In some embodiments, R is H; R¹⁵ and R¹⁸ are H;and p is 2 or 3. In some embodiments, R is H; R¹⁵ and R¹⁸ are H; and pis 2. In some embodiments, R is H; R¹⁵ and R¹⁸ are H; and p is 3. Insome embodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 2 or 3. In someembodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 2. In someembodiments, R is H; R¹⁵ and R¹⁸ are CH₃; and p is 3.

In some preferred embodiments, X is in equatorial position of

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some preferred embodiments, X is in equatorial position of

In some other preferred embodiments,

has a structure of

In some preferred embodiments, X is in equatorial position of

In some other preferred embodiments,

has a structure of

In some preferred embodiments, X is in equatorial position of

In some other preferred embodiments,

has a structure of

In some embodiments,

is

In some preferred embodiments, X is in equatorial position of

In some embodiments,

is

whereinR¹⁹ is H, D, —CN, —OH, —OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —CH₂—N(R′)₂,—S(═O)₂N(R′)₂, —C(═O)R¹, —CO₂R¹, —C(═O)N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₈heterocycloalkyl.

In some preferred embodiments, X is in equatorial position of

In some embodiments, the compound of Formula (IV) is not racemic. Insome preferred embodiments, the compound of Formula (IV) issubstantially free of other isomers. In some preferred embodiments, thecompound of Formula (IV) is substantially free of other isomers. In somepreferred embodiments, the compound of Formula (IV) comprises 25% orless of other isomers. In some preferred embodiments, the compound ofFormula (IV) comprises 20% or less of other isomers. In some preferredembodiments, the compound of Formula (IV) comprises 15% or less of otherisomers. In some preferred embodiments, the compound of Formula (IV)comprises 10% or less of other isomers. In some preferred embodiments,the compound of Formula (IV) comprises 5% or less of other isomers. Insome preferred embodiments, the compound of Formula (IV) comprises 1% orless of other isomers.

In some preferred embodiments, the compound of Formula (IV) has astereochemical purity of at least 75%. In some preferred embodiments,the compound of Formula (IV) has a stereochemical purity of at least80%. In some preferred embodiments, the compound of Formula (IV) has astereochemical purity of at least 85%. In some preferred embodiments,the compound of Formula (IV) has a stereochemical purity of at least90%. In some preferred embodiments, the compound of Formula (IV) has astereochemical purity of at least 95%. In some preferred embodiments,the compound of Formula (IV) has a stereochemical purity of at least96%. In some preferred embodiments, the compound of Formula (IV) has astereochemical purity of at least 97%. In some preferred embodiments,the compound of Formula (IV) has a stereochemical purity of at least98%. In some preferred embodiments, the compound of Formula (IV) has astereochemical purity of at least 99%.

In some preferred embodiments, the asymmetric carbon atom (CR⁷) of thecompound of Formula (IV) is present in enantiomerically enriched form.In certain embodiments, the asymmetric carbon atom (CR⁷) of the compoundof Formula (IV) has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (S)- or(R)-configuration.

In some embodiments, a compound of Formula (IV) is selected from acompound in Table 1A, Table 1B or Table 1C.

In another aspect, described herein is a compound that has the structureof Formula (V), or a pharmaceutically acceptable salt or solvatethereof:

wherein,each A is independently N or CR^(A);each R^(A) is independently selected from H, D, halogen, —CN, —OH, —OR¹,═O, ═N—OR¹, —SR¹, —S(═O)R¹, —S(═O)₂R¹, —N(R′)₂, —NR¹S(═O)(═NR¹)R²,—NR¹S(═O)₂R², —S(═O)₂N(R¹)₂, —C(═O)R¹, —OC(═O)R¹, —C(═O)OR¹, —OC(═O)OR¹,—C(═O)N(R¹)₂, —OC(═O)N(R¹)₂, —NR¹C(═O)R¹, —P(═O)(R²)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted monocyclic heteroaryl;ring Q is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, orfused bicyclic heteroaryl;X is —O—, —NR³—, —CR⁴R⁵—, —C(═O)—, —C(═CR² ₂)—, —S—, —S(═O)—, —S(═O)₂—,or —S(═O)(═NR¹)—;each R¹ is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;each R² is independently H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl,—OR¹, —N(R′)₂, —CH₂OR¹, —C(═O)OR¹, —OC(═O)R¹, —C(═O)N(R¹)₂, or—NR¹C(═O)R¹;R³ is H, —OR¹, —N(R¹)₂, substituted or unsubstituted C₁-C₆ alkyl, —CD₃,substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁴ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;R⁵ is H, D, F, —CN, —OR¹, —SR¹, —N(R′)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆alkylene-OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; orR⁴ and R⁵ taken in combination with the carbon atom to which theyattach, form a substituted or unsubstituted C₃₋₈ cycloalkyl or asubstituted or unsubstituted C₂₋₇ heterocycloalkyl;Z is CR⁷; and R⁷ is H, D, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₁-C₆ haloalkyl or —CH₂OR¹;W is substituted or unsubstituted C₁-C₄alkylene, substituted orunsubstituted C₂-C₄alkenylene, or substituted or unsubstituted C₁-C₄heteroalkylene;R is selected from the group consisting of H, a substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ fluoroalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein alkyl is optionally substituted withhydroxy, amino, substituted or unsubstituted mono-C₁₋₆ alkylamino, orsubstituted or unsubstituted di-C₁₋₆ alkylamino;R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyselected from the group consisting of H, F, OR¹, substituted orunsubstituted C₁₋₆ alkyl, a substituted or unsubstituted C₁₋₆fluoroalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, whereinalkyl is optionally substituted with hydroxy, amino, methoxy,substituted or unsubstituted mono-C₁₋₆ alkylamino or substituted orunsubstituted di-C₁₋₆ alkylamino;R¹¹ and R¹³, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group or a substituted or unsubstituted C₁₋₃heteroalkylene group; orR¹¹ and R¹⁵, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹⁶ and R¹⁷, taken in combination form a substituted or unsubstitutedC₁₋₃ alkylene group; orR¹³ and R¹⁴, taken in combination with the carbon atom to which theyattach, form a spirocyclic C₃₋₈ cycloalkyl; or R¹⁷ and R², taken incombination form a substituted or unsubstituted C₁₋₃ alkylene group; orwhen X is —NR³—, then R³ and R² are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring; orwhen X is —NR³—, then R³ and R¹⁶ are optionally taken together with theintervening atoms to which they are attached to form a 4, 5, or6-membered ring;a, b, and e are each independently selected from 0, 1, or 2; andwherein the compound of Formula (V) has a stereochemical purity of atleast 80%.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, ais 0, 1, or 2. In other embodiments, a is 0. In some other embodiments,a is 1. In some other embodiments, a is 2.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, X is —O—, —NR₃—, —S—, —CR⁴R⁵—, —C(═O)—, or —C(═CR²₂)—. In some embodiments, X is —O—. In some embodiments, X is —NR³—. Insome embodiments, X is —S—. In some embodiments, X is —CR⁴R⁵—. In someembodiments, X is —C(═O)—. In some embodiments, X is —C(═CR² ₂)—.

In some embodiments, X is —CH(CH₂OR¹)— or —CH(OR¹)—. In someembodiments, X is —CH(CH₂OR¹)—.

In some embodiments, X is-CH(OR¹)—.

In some embodiments, R³ is H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₂-C₇heterocycloalkyl.

In some embodiments, R³ is —OR¹, —N(R¹)₂, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substitutedor unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted C₂-C₇ heterocycloalkyl.

In some embodiments, ring Q is substituted or unsubstituted monocyclicaryl. In some embodiments, ring Q is substituted monocyclic aryl. Insome embodiments, ring Q is unsubstituted monocyclic aryl.

In some embodiments, ring Q is substituted phenyl. In some embodiments,ring Q is 2-hydroxy-phenyl which is substituted with: 0, 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, oxo, oxime,hydroxy, halo-C₁₋₆ alkyl, dihalo-C₁₋₆ alkyl, trihalo-C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy-C₃₋₇ cycloalkyl, halo-C₁₋₆ alkoxy, dihalo-C₁₋₆alkoxy, trihalo-C₁₋₆ alkoxy, hydroxy, cyano, halogen, amino, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, heteroaryl, C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkoxy substituted with aryl, amino, —C(═O)NH—C₁₋₆alkyl-heteroaryl, —NHC(═O)—C₁₋₆ alkylheteroaryl, C₁₋₆alkyl-C(═O)NH-heteroaryl, C₁₋₆ alkyl-NHC(═O)-heteroaryl, C₃₋₇cycloalkyl, 5-7 membered cycloalkenyl, or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms independently, selected from S, O and N.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith two C₁₋₆ alkyl. In some embodiments, two C₁₋₆ alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring.

In some embodiments, ring Q is 2-hydroxy-phenyl which is substitutedwith heteroaryl. In some embodiments, heteroaryl has 5, 6, 9, or 10 ringatoms, 1, 2 or 3 ring heteroatoms selected from N, O and S, and issubstituted with 0, 1, or 2 substituents independently selected fromoxo, hydroxy, nitro, halogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, trihalo-C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, —C(═O)NH₂, —NH₂, —NO₂, hydroxy-C₁₋₆alkylamino, hydroxy-C₁₋₆ alkyl, 4-7 membered heterocycle-C₁₋₆ alkyl,amino-C₁₋₆ alkyl, mono-C₁₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is

wherein ring P is aryl or heteroaryl. In some embodiments, ring Q is

wherein ring P is aryl. In some embodiments, ring Q is

wherein ring P is heteroaryl In some embodiments, the heteroaryl isselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is 2-naphthyl optionally substituted at the3 position with hydroxy and additionally substituted with 0, 1, or 2substituents selected from hydroxy, cyano, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkoxy, wherein the alkoxy is unsubstituted or substitutedwith hydroxy, C₁₋₆ alkoxy, amino, —NHC(═O)—C₁₋₆ alkyl, —NHC(═O)—C₁₋₆alkyl, C₁₋₆ alkylene-4-7 membered heterocycle, 4-7 membered heterocycle,mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is

In some embodiments, ring Q is

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R′)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, ring Q is monocyclic heteroaryl or fused bicyclicheteroaryl.

In some embodiments, ring Q is a 5 or 6 membered monocyclic heteroarylhaving 1-4 ring nitrogen atoms and which is substituted by phenyl or aheteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and is substituted with 0, 1, or2 substituents independently selected from cyano, C₁₋₆ alkyl, mono-C₁₋₆alkylamino, di-C₁₋₆ alkylamino, hydroxy-C₁₋₆ alkylamino, hydroxy-C₁₋₆alkyl, amino-C₁₋₆ alkyl and mono-C₁₋₆ alkylamino-C₁₋₆ alkyl, and di-C₁₋₆alkylamino-C₁₋₆ alkyl.

In some embodiments, ring Q is a 5 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a 6 membered monocyclic heteroarylselected from the group consisting of:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 0, 1, 2, or 3.

In some embodiments, ring Q is a fused bicyclic heteroaryl having 8 to10 ring atoms, 1, 2, or 3 ring heteroatoms independently selected fromN, O or S, and which is substituted with 0, 1, or 2 substituentsindependently selected from cyano, oxime, halogen, hydroxy, C₁₋₆ alkyl,C₂₄ alkenyl, C₂₄ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted withhydroxy, amino, mono-C₁₋₆ alkylamino, and di-C₁₋₆ alkylamino.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, 5-6 fused heteroaryl, 5-5 fused heteroaryl, 7-5 fusedheteroaryl, or 5-7 fused heteroaryl.

In some embodiments, ring Q is a 6-5 fused heteroaryl, 6-6 fusedheteroaryl, or 5-6 fused heteroaryl, selected from the group consistingof:

whereineach R^(B) is independently selected from cyano, halogen, hydroxy,substituted or unsubstituted C₁₋₆ alkyl, —OCH₃, —OCD₃, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₁₋₆ alkoxy, substituted or unsubstitutedC₃. cycloalkyl, substituted or unsubstituted C₂₋₈ heterocycloalkyl,heteroaryl, substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl-aryl, substituted orunsubstituted C₁₋₆ alkyl-heterocycloalkyl, substituted or unsubstitutedC₁₋₆ alkyl-heteroaryl, substituted or unsubstituted C₁₋₆ alkoxy-aryl,substituted or unsubstituted C₁₋₆ alkoxy-heterocycloalkyl, substitutedor unsubstituted C₁₋₆ alkoxy-heteroaryl, and C₁₋₆ alkoxy substitutedwith hydroxy, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino and di-C₁₋₆alkylamino; and m is 1, 2, or 3.

In some embodiments, ring Q is

and each R⁶ is independently H, —OR¹, —N(R¹)₂, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl,substituted or unsubstituted C₁-C₆ heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂—C₇heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁶ are taken together with the N atomto which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl. In some embodiments, each R⁶ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl. Insome embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₄ alkyl, or substituted or unsubstituted C₃-C₆cycloalkyl.

In some embodiments, X is —NR³—.

In some embodiments, R³ is —OR¹, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, or substituted or unsubstituted C₃-C₈cycloalkyl.

In some embodiments, R³ is —OR¹. In some embodiments, R³ is —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH or —OCH₂CH₂OCH₃. In some embodiments, R³ is —OCH₃.In some embodiments, R³ is —OCH₂CH₃. In some embodiments, R³ is—OCH₂CH₂CH₃. In some embodiments, R³ is —OCH(CH₃)₂. In some embodiments,R³ is —OCD₃.

In some embodiments, R³ is-CD₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆ haloalkyl.In some embodiments, R³ is CF₃. In some embodiments, R³ is —CH₂CH₂F. Insome embodiments, R³ is —CH₂CH₂CH₂F. In some embodiments, R³ is —CH₂CF₃.In some embodiments, R³ is —CH₂CH₂CF₃.

In some embodiments, R³ is-CH₃ or —CF₃.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R³ is —OCH₂CH₂OCH₃ or —OCH₂CH₂OCF₃. Insome embodiments, R³ is —CH₂CH₂OCH₃.

In some embodiments, R³ is substituted or unsubstituted C₃-C₈cycloalkyl. In some embodiments, R³ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In someembodiments, R³ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In some embodiments, R³ is cyclopropyl. In some embodiments, R³ iscyclobutyl. In some embodiments, R³ is cyclopentyl. In some embodiments,R³ is cyclohexyl.

In some embodiments, R³ is cyclopentenyl, cyclohexenyl, cycloheptenyl,or cyclooctenyl. In some embodiments, R³ is cyclopentenyl orcyclohexenyl. In some embodiments, R³ is cyclopentenyl. In someembodiments, R³ is cyclohexenyl.

In some embodiments,

is

wherein p is 1, 2, or 3.

In some preferred embodiments, X is in equatorial position of

In some embodiments,

is

In some embodiments,

is

In some preferred embodiments, X is in equatorial position of

In some other preferred embodiments,

has a structure of

In some embodiments,

is

wherein p is 1, 2, or 3.

In some preferred embodiments, X is in equatorial position of

In some embodiments

is

In some embodiments,

is

In some embodiments,

is

wherein W is —CH₂OCH₂—.

In some preferred embodiments, X is in equatorial position of

wherein W is —CH₂OCH₂—.

In some embodiments,

is

wherein W is —CH₂N(R¹⁹)CH₂—, wherein R¹⁹ is H, D, —CN, —OH, —OR¹, —SR¹,—S(═O)R¹, —S(═O)₂R¹, —CH₂—N(R′)₂, —S(═O)₂N(R′)₂, —C(═O)R¹, —CO₂R¹,—C(═O)N(R′)₂, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted C₂-C₈ heterocycloalkyl.

In some preferred embodiments, X is in equatorial position of

wherein W is —CH₂N(R¹⁹)CH₂—.

In some embodiments, the compound of Formula (V) is not racemic. In somepreferred embodiments, the compound of Formula (V) is substantially freeof other isomers. In some preferred embodiments, the compound of Formula(V) is a single isomer substantially free of other isomers. In somepreferred embodiments, the compound of Formula (V) comprises 25% or lessof other isomers. In some preferred embodiments, the compound of Formula(V) comprises 20% or less of other isomers. In some preferredembodiments, the compound of Formula (V) comprises 15% or less of otherisomers. In some preferred embodiments, the compound of Formula (V)comprises 10% or less of other isomers. In some preferred embodiments,the compound of Formula (V) comprises 5% or less of other isomers. Insome preferred embodiments, the compound of Formula (V) comprises 1% orless of other isomers.

In some preferred embodiments, the compound of Formula (V) has astereochemical purity of at least 75%. In some preferred embodiments,the compound of Formula (V) has a stereochemical purity of at least 80%.In some preferred embodiments, the compound of Formula (V) has astereochemical purity of at least 85%. In some preferred embodiments,the compound of Formula (V) has a stereochemical purity of at least 90%.In some preferred embodiments, the compound of Formula (V) has astereochemical purity of at least 95%. In some preferred embodiments,the compound of Formula (V) has a stereochemical purity of at least 96%.In some preferred embodiments, the compound of Formula (V) has astereochemical purity of at least 97%. In some preferred embodiments,the compound of Formula (V) has a stereochemical purity of at least 98%.In some preferred embodiments, the compound of Formula (V) has astereochemical purity of at least 99%.

In some embodiments, the asymmetric carbon atom (CR⁷) of the compound ofFormula (V) is present in enantiomerically enriched form. In certainembodiments, the asymmetric carbon atom (CR⁷) of the compound of Formula(V) has at least 50% enantiomeric excess, at least 60% enantiomericexcess, at least 70% enantiomeric excess, at least 80% enantiomericexcess, at least 90% enantiomeric excess, at least 95% enantiomericexcess, or at least 99% enantiomeric excess in the (S)- or(R)-configuration.

In some embodiments, a compound of Formula (V) is selected from acompound in Table 1A, Table 1B or Table 1C

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, a compound of Formula (I), (II), (III), (IV) or (V)is selected from:

-   (6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(piperazin-1-yl)methanone;-   2-(6-(piperidin-4-ylthio)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   (3,6-diazabicyclo[3.1.1]heptan-3-yl)(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methanone;-   2-(6-((6-azabicyclo[3.1.1]heptan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   (3,8-diazabicyclo[3.2.1]octan-3-yl)(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methanone;-   2-(6-((8-azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(octahydro-1,6-naphthyridin-1(2H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(methoxy(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(hydroxy(2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   (6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(3,3,5,5-tetramethylpiperazin-1-yl)methanone;-   (6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2,2,6,6-tetramethylpiperidin-4-yl)methanone;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)thio)pyridazin-3-yl)phenol;-   2-(6-((2-methoxyethoxy)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-ylidene)methyl)pyridazin-3-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)(trifluoromethyl)amino)pyridazin-3-yl)phenol;-   2-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)(2,2,2-trifluoroethyl)amino)pyridazin-3-yl)phenol;-   2-(6-((3-fluoropropyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)(3,3,3-trifluoropropyl)amino)pyridazin-3-yl)phenol;-   3-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-methoxynaphthalen-2-ol;-   2-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(4-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   5-(4-(6-((2-fluoroethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyrimidin-2(1H)-one;-   2-(6-((2-methoxyethoxy)(2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-5-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-3-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-methoxynaphthalen-2-ol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-1-methylisoquinolin-7-ol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)thio)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methanone;-   2-(6-(1-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)vinyl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(3-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-amino-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-amino-5-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-amino-3-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-7-methoxynaphthalen-2-ol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)naphthalene-2,7-diol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)isoquinolin-7-ol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-1-methylisoquinolin-7-ol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1H-pyrazol-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3-difluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(2-methoxypyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(2-methoxypyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3-difluoro-5-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3-fluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3,4-difluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3-fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1,2,3-triazin-5-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1,2,3-triazin-5-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(1,2,3-triazin-5-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3,4-difluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2,3-difluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3-difluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-4-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-5-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-4-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-5-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   7-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N-methylisoquinoline-3-carboxamide;-   7-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N-methylisoquinoline-3-carboxamide;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-1-fluoro-7-hydroxy-N-methyl-2-naphthamide;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-7-hydroxy-N-methyl-2-naphthamide;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-fluoro-7-hydroxy-N-methyl-2-naphthamide;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-1-fluoro-7-hydroxy-N-methyl-2-naphthamide;-   2-(6-(cyclopropyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(cyclobutyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(1,7-diazaspiro[3.5]nonan-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-((2-methoxyethyl)(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrimidin-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridin-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(methyl((3R,5r,6S)-octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(methyl((3R,5s,6S)-octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,4R,5S)-2-azabicyclo[2.2.1]heptan-5-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3r,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3r,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7r)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7r)-1,5-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7s)-1,5-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,5S,7r)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)quinolin-7-ol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-7-methoxynaphthalen-2-ol;-   6-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-hydroxy-3-methylbenzo[d]oxazol-2(3H)-one;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-7-(fluoromethoxy)naphthalen-2-ol;-   3-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-7-(difluoromethoxy)naphthalen-2-ol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-(methyl-d3)-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methoxypyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-(fluoromethyl)-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-fluoro-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-fluoro-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-1-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-hydroxy-2-methylphenyl)-1-methylpyridin-2(1H)-one;-   5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methyl-1,3,5-triazin-2(1H)-one;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-methyl-5-(1H-pyrazol-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)pyridin-2(1H)-one;-   5-(2-(difluoromethoxy)pyridin-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;-   6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-hydroxy-N-methylbenzofuran-2-carboxamide;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-fluoro-6-methoxypyridin-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-6-fluoropyridin-2-ol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;-   5-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N-methylbenzofuran-2-carboxamide;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;-   6-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carbonitrile;-   1-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1H-imidazole-4-carbonitrile;-   1-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1H-imidazole-4-carbonitrile;-   6-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)picolinonitrile;-   1-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1H-pyrazole-4-carbonitrile;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(ethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(ethyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   1-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1H-pyrrole-3-carbonitrile;-   5-(2,6-difluoropyridin-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-fluoro-6-(methoxy-d3)pyridin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(2-fluoro-6-(methoxy-d3)pyridin-4-yl)phenol;-   4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3′-methoxy-[1,1′-biphenyl]-3-ol;-   4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4′-fluoro-3′-methoxy-[1,1′-biphenyl]-3-ol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methoxypyridin-3-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-fluoro-5-methoxypyridin-3-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(3-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2H-1,2,3-triazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-methyl-1H-1,2,3-triazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-1,2,3-triazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-tetrazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(3-methylisoxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2,4-dimethyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1H-tetrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4H-1,2,4-triazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methylpyridin-3-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methylpyrimidin-5-yl)phenol;-   5-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methylpyridazin-3-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   5-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-1,2,4-triazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(3-methyl-1H-1,2,4-triazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl-1H-pyrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(2H-1,2,3-triazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-tetrazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(3-methylisoxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1H-tetrazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   5-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N-methylbenzofuran-2-carboxamide;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   6-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyrimidin-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(2-methyloxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2H-1,2,3-triazol-2-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;-   5-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   5-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-(methyl-d3)pyridazin-3(2H)-one;-   5-(4-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-2-(methyl-d3)pyridazin-3(2H)-one;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-(methyl-d3)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;-   5-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-2-methylpyridazin-3(2H)-one;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-(methyl-d3)-1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-methoxypyridin-4-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1,6-dimethylpyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;-   4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3′-methoxy-4′-methyl-[1,1′-biphenyl]-3-ol;-   4-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   6-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-hydroxy-N-methylbenzofuran-2-carboxamide;-   6-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide;-   6-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-N-cyclopropyl-5-hydroxybenzofuran-2-carboxamide;-   5-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N-methylbenzofuran-2-carboxamide;-   5-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-6-hydroxy-N,N-dimethylbenzofuran-2-carboxamide;-   5-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-N-cyclopropyl-6-hydroxybenzofuran-2-carboxamide;-   6-(4-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;-   2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenol;-   2-(6-(cyclopropyl((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(2-(methyl-d3)oxazol-5-yl)phenol;-   2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(2-(methyl-d3)oxazol-5-yl)phenol;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;-   4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)pyridin-2(1H)-one;-   5-(2-(difluoromethoxy)pyridin-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)phenol;-   3-amino-1-(4-(cyclopropyl(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)thio)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-((1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-((1R,5S)-6-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)propan-1-one;-   3-amino-1-(4-(cyclobutyl(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methoxy)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(1-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)propan-1-one;-   3-amino-1-(1-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)octahydro-1,6-naphthyridin-6(2H)-yl)propan-1-one;-   3-amino-1-(1-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-1,7-diazaspiro[3.5]nonan-7-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)thio)piperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2-methoxyethoxy)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methylene)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)piperidin-1-yl)propan-1-one;-   3-amino-1-(4-(hydroxy(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methyl)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methoxy)methyl)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)-2,2,6,6-tetramethylpiperazin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(trifluoromethyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((2-fluoroethyl)(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2,2,2-trifluoroethyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((3-fluoropropyl)(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2-methoxyethyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-((1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-((1R,3r,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-((1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-((1R,3r,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-(3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;-   3-amino-1-(4-((5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(methyl)amino)piperidin-1-yl)propan-1-one;-   3-amino-1-(4-((5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((5-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)oxy)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   3-amino-1-(4-((2-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyrimidin-5-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   5-(4-(5-((1-(3-aminopropanoyl)-2,2,6,6-tetramethylpiperidin-4-yl)(methyl)amino)pyrazin-2-yl)-3-hydroxyphenyl)pyrimidin-2(1H)-one;-   1-(4-((4-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)-3-hydroxyphenyl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)-3-aminopropan-1-one;-   2′-(4-((1-(3-aminopropanoyl)piperidin-4-yl)(methyl)amino)-2-hydroxyphenyl)-[5,5′-bipyrimidin]-2(1H)-one;-   (E)-3-(4-aminophenyl)-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)prop-2-en-1-one;-   3-(4-aminophenyl)-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one;-   1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)-2-(piperidin-4-yl)ethan-1-one;-   4-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidine-1-carbonyl)cyclohexane-1-carboxylic    acid;-   1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)-2-(2-(methylamino)ethoxy)ethan-1-one;-   4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)aamino)-2,2,6,6-tetramethyl-N-(3-(methylamino)propyl)piperidine-1-carboxamide;-   (4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)(piperidin-4-yl)methanone;-   1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)-2-(methyl(2-(methylamino)ethyl)amino)ethan-1-one;-   2-(azetidin-3-yl)-1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1-one;-   1-(4-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)pent-4-yn-1-one.

Exemplary SMSM compounds are summarized in Table 1A, Table 1B and Table1C.

TABLE 1A Exemplary SMSM compounds SMSM # Structure Name 1

(6-(2-hydroxy-4-(1H-pyrazol-4- yl)phenyl)pyridazin-3-yl)(piperazin-1-yl)methanone 2

2-(6-(piperidin-4-ylthio)pyridazin-3- yl)-5-(1H-pyrazol-4-yl)phenol 3

(3,6-diazabicyclo[3.1.1]heptan-3-yl)(6- (2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methanone 4

2-(6-((6-azabicyclo[3.1.1]heptan-3- yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol 5

(3,8-diazabicyclo[3.2.1]octan-3-yl)(6- (2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methanone 6

2-(6-((8-azabicyclo[3.2.1]octan-3- yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol 7

2-(6-(octahydro-1,6-naphthyridin- 1(2H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol 8

2-(6-(methoxy(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 9

2-(6-(hydroxy (2,2,6,6- tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 10

(6-(2-hydroxy-4-(1H-pyrazol-4- yl)phenyl)pyridazin-3-yl)(3,3,5,5-tetramethylpiperazin-1-yl)methanone 11

(6-(2-hydroxy-4-(1H-pyrazol-4- yl)phenyl)pyridazin-3-yl)(2,2,6,6-tetramethylpiperidin-4-yl)methanone 12

5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-yl)thio)pyridazin-3-yl)phenol 13

2-(6-((2-methoxyethoxy)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 14

5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-ylidene)methyl)pyridazin-3-yl)phenol 15

5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-yl)(trifluoromethyl)amino)pyridazin-3- yl)phenol 16

2-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 17

5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-yl)(2,2,2-trifluoroethyl)amino)pyridazin-3- yl)phenol 18

2-(6-((3-fluoropropyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 19

5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-yl)(3,3,3-trifluoropropyl)amino)pyridazin-3- yl)phenol 20

3-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7- methoxynaphthalen-2-ol 21

2-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl- 1H-pyrazol-4-yl)phenol 22

2-(6-((2-fluoroethyl)(2,2,6,6- yl)amino)pyridazin-3-yl)-5-(5-methyl-1H-pyrazol-4-yl)phenol 23

2-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 24

2-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-1-yl)phenol 25

5-(4-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3- hydroxyphenyl)pyridin-2(1H)-one 26

5-(4-(6-((2-fluoroethyl)(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3- hydroxyphenyl)pyrimidin-2(1H)-one 27

2-(6-((2-methoxyethoxy)(2,2,6,6- tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 28

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol- 4-yl)phenol 29

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 30

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-methyl- 1H-imidazol-1-yl)phenol 31

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H- imidazol-1-yl)phenol 32

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl- 1H-pyrazol-4-yl)phenol 33

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl- 1H-pyrazol-4-yl)phenol 34

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol- 1-yl)phenol 35

4-(4-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3- hydroxyphenyl)pyridin-2(1H)-one 36

4-(4-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3- hydroxyphenyl)-1-methylpyridin- 2(1H)-one 37

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-1H- pyrazol-1-yl)phenol 38

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-5- methyl-1H-pyrazol-1-yl)phenol 39

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(4-amino-3- methyl-1H-pyrazol-1-yl)phenol 40

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl- 1,3,4-oxadiazol-2-yl)phenol 41

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl- 1,3,4-thiadiazol-2-yl)phenol 42

3-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3- yl)oxy)pyridazin-3-yl)-7-methoxynaphthalen-2-ol 43

3-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)naphthalene-2,7- diol 44

6-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol 45

6-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3- yl)oxy)pyridazin-3-yl)-1-methylisoquinolin-7-ol 46

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 47

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)thio)pyridazin-3-yl)-5-(1H-pyrazol- 4-yl)phenol 48

((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(6-(2-hydroxy-4-(1H-pyrazol-4- yl)phenyl)pyridazin-3-yl)methanone49

2-(6-(1-((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)vinyl)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 50

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 51

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4- methyl-1H-imidazol-1-yl)phenol 52

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5- (1H-imidazol-1-yl)phenol 53

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(3- methyl-1H-pyrazol-4-yl)phenol 54

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol 55

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5- (1H-pyrazol-1-yl)phenol 56

4-(4-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- hydroxyphenyl)pyridin-2(1H)-one 57

4-(4-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- hydroxyphenyl)-1-methylpyridin-2(1H)-one 58

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4- amino-1H-pyrazol-1-yl)phenol 59

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4- amino-5-methyl-1H-pyrazol-1-yl)phenol 60

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(4- amino-3-methyl-1H-pyrazol-1-yl)phenol 61

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 62

2-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol 63

3-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-7- methoxynaphthalen-2-ol 64

3-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3- yl)naphthalene-2,7-diol 65

6-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3- yl)isoquinolin-7-ol 66

6-(6-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-1- methylisoquinolin-7-ol 67

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(1H-pyrazol-4-yl)phenol 68

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(1H-pyrazol-4-yl)phenol69

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one 70

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3- difluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one 71

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(2-methoxypyridin-4-yl)phenol 72

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(2-methoxypyridin-4-yl)phenol 73

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-methoxypyridazin-4-yl)phenol 74

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(6-methoxypyridazin-4-yl)phenol 75

5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-hydroxyphenyl)-2-methylpyridazin-3(2H)-one 76

5-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3- difluoro-5-hydroxyphenyl)-2-methylpyridazin-3(2H)-one 77

2-(6-(cyclopropyl((1R,3s,5S)-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)amino)pyridazin-3-yl)-3-fluoro-5-(6- methoxypyridazin-4-yl)phenol 78

2-(6-(cyclopropyl((1R,3s,5S)-1,5- dimethyl-8-azabicyclo[3.2.1]octan-3-yl)amino)pyridazin-3-yl)-3,4-difluoro- 5-(6-methoxypyridazin-4-yl)phenol79

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-methoxypyrimidin-4-yl)phenol 80

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(6-methoxypyrimidin-4-yl)phenol 81

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 82

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-4- fluoro-5-(1H-pyrazol-4-yl)phenol 83

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3- fluoro-5-(1H-pyrazol-4-yl)phenol 84

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1H-pyrazol-4-yl)phenol 85

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol 86

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(2-(methoxy-d3)pyridin-4- yl)phenol 87

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol 88

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(6-(methoxy-d3)pyridazin- 4-yl)phenol 89

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3-fluoro-5- (2-(methoxy-d3)pyridin-4-yl)phenol90

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3,4-difluoro-5-(2-(methoxy-d3)pyridin-4-yl)phenol 91

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3-fluoro-5-(6-(methoxy-d3)pyridazin-4-yl)phenol 92

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl-d3)amino)pyridazin-3-yl)-3,4-difluoro- 5-(6-(methoxy-d3)pyridazin-4-yl)phenol 93

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenol 94

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(1-methyl-1H-pyrazol-4-yl)phenol 95

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4- fluoro-5-(1,2,3-triazin-5-yl)phenol96

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4-difluoro-5-(1,2,3-triazin-5-yl)phenol 97

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(1,2,3-triazin-5-yl)phenol98

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4- fluoro-5-(6-methoxypyridazin-4-yl)phenol 99

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(6-methoxypyridazin-4-yl)phenol 100

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-methoxypyridazin-4-yl)phenol 101

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(6-methoxypyrimidin-4-yl)phenol 102

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-methoxypyrimidin-4-yl)phenol 103

2-(6-(cyclopropyl((1R,3s,5S)-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-4-fluoro-5-(6- methoxypyridazin-4-yl)phenol 104

2-(6-(cyclopropyl((1R,3s,5S)-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-3,4-difluoro- 5-(6-methoxypyridazin-4-yl)phenol105

2-(6-(cyclopropyl((1R,3s,5S)-1,5- dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyridazin-3-yl)-3-fluoro-5-(6- methoxypyridazin-4-yl)phenol 106

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-4- fluoro-5-(6-methoxypyridazin-4-yl)phenol 107

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3,4- difluoro-5-(6-methoxypyridazin-4-yl)phenol 108

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(2-fluoroethyl)amino)pyridazin-3-yl)-3- fluoro-5-(6-methoxypyridazin-4-yl)phenol 109

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-4-fluoro-5-(6- methoxypyridazin-4-yl)phenol 110

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3,4-difluoro-5- (6-methoxypyridazin-4-yl)phenol111

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-fluoro-5-(6- methoxypyridazin-4-yl)phenol 112

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2-fluoro-5- hydroxyphenyl)-1-methylpyridin-2(1H)-one 113

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2,3-difluoro-5- hydroxyphenyl)-1-methylpyridin-2(1H)-one 114

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-fluoro-5- hydroxyphenyl)-1-methylpyridin-2(1H)-one 115

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2- fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one 116

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2,3- difluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one 117

4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one 118

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-4-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol 119

2-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-5-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol 120

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-4-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol 121

2-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-5-fluoropyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol 122

7-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-6- hydroxy-N-methylisoquinoline-3-carboxamide 123

7-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-6- hydroxy-N-methylisoquinoline-3-carboxamide 124

6-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-7- hydroxy-N-methylquinoline-2-carboxamide 125

6-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-1- fluoro-7-hydroxy-N-methyl-2-naphthamide 126

6-(6-(((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-7-hydroxy-N-methyl-2-naphthamide 127

6-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3- fluoro-7-hydroxy-N-methyl-2-naphthamide 128

6-(6-(((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-1- fluoro-7-hydroxy-N-methyl-2-naphthamide

TABLE 1B Exemplary SMSM compounds A-673 Splice Splice SMSM IC₅₀ EC₅₀IC₅₀ M + H # (nM)^(A) (nM)^(B) (nM)^(C) Structure Name Proton NMR (MS)129 251- 500

2-(6- (cyclopropyl(2, 2,6,6- tetramethylpiper- idin-4- yl)amino)pyrid-azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.79(s, 1H), 12.99 (s, 1H), 8.25 (d, J = 9.8 Hz, 1H), 8.23- 7.96 (m, 2H),7.85 (d, J = 8 Hz, 1H), 7.58 (d, J = 9.8 Hz, 1H), 7.26-7.16 (m, 2H),5.04-4.72 (m, 1H), 2.62-2.53 (m, 1H), 1.80-1.61 (m, 4H), 1.23 (s, ₆ h),1.09 (s, ₆ h), 1.03- 433.2 0.94 (m, 2H), 0.70- 0.59 (m, 2H).130 >1000 >1000 >1000

2-(6- (cyclobutyl(2,2, 6,6- tetramethylpiper- idin-4- yl)amino)pyrid-azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ8.06 (d, J = 10 Hz, 1H), 8.02 (s, 2H), 7.78-7.74 (m, 1H), 7.32 (d, J =10 Hz, 1H), 7.19 (s, 2H), 4.47-4.29 (m, 2H), 2.48-2.32 (m, 4H),2.29-2.16 (m, 2H), 1.90-1.77 (m, 2H), 1.73- 1.64 (m, 2H), 1.38 (s, ₆ h),1.26 (s, ₆ h). 447.2 131 >1000 101- 250 251- 500

2-(6- (octahydro-1H- pyrrolo[3,2- c]pyridin-1- yl)pyridazin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (400 MHz, methanol-d₄) δ 8.11 (d,J = 8 Hz, 1H), 7.91 (s, 2H), 7.64 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 8Hz, 1H), 7.12-7.08 (m, 2H), 4.35-4.31(m, 1H), 3.70-3.20 (m, 5H),3.04-2.98 (m, 1H), 2.80-1.70 (m, ₇ h). 363.2 132 >1000

2-(6-(1,7- diazaspiro[3.5] nonan-1- yl)pyridazin-3- yl)-5-(1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ 8.27 (d, J = 9.6Hz, 1H), 8.05 (s, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 8.2, 1.7Hz 1H), 7.23 (q, J = 4.0 Hz, 2H), 4.20-4.17 (m, 2H), 3.55-3.52 (m, 2H),3.18-3.08 (m, 2H), 2.92-2.84 (m, 2H), 2.52 363.2 (t, J = 7.5 Hz, 2H),2.24- 2.21 (m, 2H). 133 >1000 501- 1000 >1000

2-(6-((2- methoxyethyl) (2,2,6,6- tetramethylpiper- idin-4-yl)amino)pyrid- azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.06 (d, J = 9.9 Hz, 1H), 8.01 (s, 2H), 7.75 (d, J = 8.6Hz, 1H), 7.37 (d, J = 9.9 Hz, 1H), 7.24-7.13 (m, 2H), 5.07-4.96 (m, 1H),3.72- 3.56 (m, 4H), 3.40 (s, ₃ h), 1.87-1.69 (m, 4H), 1.46 (s, ₆ h),1.31 (s, ₆ h). 451.3 134 >1000 >1000 >1000

2-(5- (methyl(2,2,6,6- tetramethylpiper- idin-4- yl)amino)pyrim-idin-2-yl)-5- (1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ8.46 (s, 2H), 8.28 (d, J = 8.2 Hz, 1H), 8.01 (s, 2H), 7.20- 7.10 (m,2H), 4.26-4.23 (m, 1H), 2.92 (s, ₃ h), 1.76-1.72 (m, 2H), 1.57- 1.52 (m,2H), 1.39 (s, ₆ h), 1.25 (s, ₆ h). 407.4 135 >1000 >1000 >1000

2-(5- (methyl(2,2,6,6- tetramethylpiper- idin-4- yl)amino)pyridin-2-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ 8.17(d, J = 3.0 Hz, 1H), 7.98 (s, 2H), 7.93 (d, J = 9.1 Hz, 1H), 7.79 (d, J= 8.3 Hz, 1H), 7.45 (dd, J = 9.2, 3.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H),7.11 (s, 1H), 4.26-4.23 (m, 1H), 2.90 (s, ₃ h), 1.77-1.73 406.1 (m, 2H),1.60-1.53 (m, 2H), 1.42 (s, ₆ h), 1.32 (s, 1H), 1.27 (s, ₆ h). 136 501-1000 101- 250 251- 500

2-(5- (methyl(2,2,6,6- tetramethylpiper- idin-4- yl)amino)pyrazin-2-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ 8.72(d, J = 1.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.86 (s, 2H), 7.70 (d, J= 8.3 Hz, 1H), 7.09-7.02 (m, 1H), 7.01 (d, J = 1.8 Hz, 1H), 5.08 (t, J =12.5 Hz, 1H), 2.90 (s, ₃ h), 1.61-1.44 (m, 4H), 1.30 (s, ₆ h), 407.31.16 (s, ₆ h). 137 >1000 >1000 >1000

2-(6- (((1R,5S,6s)-3- azabicyclo[3.1.0] hexan-6- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ13.78 (s, 1H), 12.99 (s, 1H), 8.34- 7.95 (m, 4H), 7.83 (d, J = 8.1 Hz,1H), 7.42 (d, J = 9.8 Hz, 1H), 7.21 (s, 2H), 3.17 (s, ₃ h), 3.11 (d, J =11.2 Hz, 2H), 2.77 (d, J = 11.0 Hz, 2H), 2.54-2.51 (m, 1H), 1.76 349.1(s, 2H). 138 10- 100 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.12 (d, J = 9.8 Hz, 1H), 8.02 (s, 2H), 7.77 (d, J = 8.3Hz, 1H), 7.33 (d, J = 9.9 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 5.23-5.07(m, 1H), 3.88-3.86 (m, 2H), 3.02 (s, ₃ h), 2.14-2.00 (m, ₆ h), 1.83-1.81(m, 2H). 377.2 139 >1000 >1000 >1000

2-(6- (((1R,3r,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 7.99 (s, 2H), 7.72-7.64 (m, 1H), 7.60 (d, J = 8.2 Hz,1H), 7.21-7.07 (m, ₃ h), 3.91- 3.81 (m, ₃ h), 3.71 (s, ₃ h), 2.68-2.58(m, 2H), 2.34-2.17 (m, 2H), 2.03- 1.94 (m, 2H), 1.86- 1.75 (m, 2H).377.2 140 101- 250 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ 8.28(d, J = 9.5 Hz, 1H), 8.03 (s, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.26-7.19(m, ₃ h), 5.61-5.57 (m, 1H), 3.68 (s, 2H), 2.34-2.31 (m, 2H), 1.95 (s,4H), 1.80- 1.74 (m, 2H). 364.2 141 >1000 >1000 >1000

2-(6- (((1R,3r,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ 8.32(d, J = 9.6 Hz, 1H), 8.04 (s, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.31 (d, J= 9.5 Hz, 1H), 7.25-7.20 (m, 2H), 5.53-5.50 (m, 1H), 3.57 (s, 2H),2.23-2.09 (m, ₆ h), 1.96-1.82 (m, 2H). 364.0 142 >1000 251- 500 501-1000

2-(6- (methyl((3R,5r, 6S)- octahydrocyclo- penta[c]pyrrol- 5-yl)amino)pyrid- azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.09 (d, J = 10.1 Hz, 1H), 8.02 (s, 2H), 7.76 (d, J = 8.5Hz, 1H), 7.37 (d, J = 9.6 Hz, 1H), 7.23-7.17 (m, 2H), 4.77-4.70 (m, 1H),3.08 (s, ₃ h), 2.97-2.71 (m, ₆ h), 2.18-2.03 (m, 2H), 1.70-1.51 (m, 2H).377.2 143 >1000 251- 500 501- 1000

2-(6- (methyl((3R,5s, 6S)- octahydrocyclo penta[c]pyrrol- 5-yl)amino)pyrid- azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.11 (d, J = 9.9 Hz, 1H), 8.02 (s, 2H), 7.79-7.75 (m,1H), 7.39 (d, J = 9.9 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 5.07-4.99 (m,1H), 3.31- 3.25 (m, 2H), 3.05 (s, ₃ h), 2.87-2.81 (m, 2H), 2.78-2.72 (m,2H), 2.10- 377.2 2.00 (m, 2H), 1.81- 1.73 (m, 2H). 144 501- 1000 >1000>1000

2-(6- (((1R,5S,8s)-3- azabicyclo[3.2.1] octan-8- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ13.87 (s, 1H), 12.98 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H), 8.10 (s, 2H),7.83 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 9.9 Hz, 1H), 7.23-7.16 (m, 2H),3.93 (s, 1H), 3.11 (s, ₃ h), 2.88-2.82 (m, 2H), 2.72-2.65 (m, 377.2 2H),2.28 (s, 2H), 1.80- 1.63 (m, 4H). 145 >1000 >1000 >1000

2-(6- (((1R,5S,8r)-3- azabicyclo[3.2.1] octan-8- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ13.74 (s, 1H), 12.99 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 8.13 (s, ₃ h),7.89 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 9.8 Hz, 1H), 7.24-7.19 (m, 2H),3.69-3.63 (m, 1H), 3.19 (s, ₃ h), 2.93-2.86 (m, 2H), 2.71 (s, 2H), 377.22.47-2.40 (m, 2H), 1.86- 1.71 (m, 4H). 146 >1000 101- 250 251- 500

2-(6- (((1R,4R,5S)-2- azabicyclo[2.2.1] heptan-5- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.15 (d, J = 9.9 Hz, 1H), 8.02 (s, 2H), 7.79 (d, J = 8.8Hz, 1H), 7.45 (d, J = 9.8 Hz, 1H), 7.25-7.15 (m, 2H), 4.41-4.39 (m, 1H),3.77 (s, 1H), 3.23 (s, ₃ h), 3.22- 3.97 (m, ₃ h), 2.33- 1.77 (m, 4H).363.1 147 >1000 101- 250 251- 500

2-(6- (((1S,4S,5R)-2- azabicyclo[2.2.1] heptan-5- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.15 (d, J = 9.9 Hz, 1H), 8.02 (s, 2H), 7.79 (d, J = 8.9Hz, 1H), 7.45 (d, J = 9.8 Hz, 1H), 7.25-7.15 (m, 2H), 4.41-4.38 (m, 1H),3.78 (s, 1H), 3.22 (s, ₃ h), 3.22- 3.97 (m, ₃ h), 2.33- 1.78 (m, 4H).363.1 148 >1000 >1000 >1000

2-(6- (((1R,4R,5R)-2- azabicyclo[2.2.1] heptan-5- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.09 (d, J = 10.0 Hz, 1H), 8.02 (s, 2H), 7.75 (d, J = 8.8Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H) 7.20-7.19 (m, 2H), 4.41-4.39 (m, 1H),3.87 (s, 1H), 3.14 (s, ₃ h), 3.11- 2.83 (m, ₃ h), 2.41- 1.77 (m, 4H).363.1 149 >1000 251- 500 >1000

2-(6- (((1S,4S,5S)-2- azabicyclo[2.2.1] heptan-5- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.09 (d, J = 10.0 Hz, 1H), 8.02 (s, 2H), 7.75 (d, J = 8.8Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.20-7.19 (m, 2H), 4.41-4.39 (m, 1H),3.87 (s, 1H), 3.14 (s, ₃ h), 3.11- 2.83 (m, ₃ h), 2.41- 1.77 (m, 4H).363.1 150 >1000

2-(6- (((1R,3r,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO- d₆) δ 13.83 (s, 1H), 12.99 (s, 1H), 8.20 (d, J = 10.0Hz, ₃ h), 7.84 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.25- 7.09(m, 2H), 4.93-4.88 (m, 1H), 2.93 (s, ₃ h), 1.84-1.75 (m, 2H), 1.60- 1.51(m, ₆ h), 1.19 (s, ₆ h). 405.2 151 <10 <10 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)ami- no)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(400 MHz, DMSO- d₆) δ 13.87 (s, 1H), 12.99 (s, 1H), 8.20- 7.95 (m, 2H),7.83 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 9.9 Hz, 1H), 7.24- 7.05 (m, 2H),4.91-4.88 (m, 1H), 2.92 (s, ₃ h), 1.86-1.64 (m, 4H), 1.58-1.50 (m, 4H),1.24 405.2 (s, ₆ h). 152 101- 250 10- 100 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)oxy)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.04 (s, 2H), 8.44 (d, J = 9.6 Hz, 1H), 8.15 (s, 2H), 7.92(d, J = 8.4 Hz, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.27- 7.20 (m, 2H), 5.54-5.44 (m, 1H), 2.18-2.11 (m, 2H), 1.91 (s, 1H), 392.2 1.80-1.74 (m, 2H),1.51- 1.45 (m, 2H), 1.37 (t, J = 11.3 Hz, 2H), 1.18 (s, ₆ h).153 >1000 >1000 >1000

2-(6- (((1R,3r,5S) 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)oxy)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.27 (s, 1H), 13.02 (s, 1H), 8.45 (d, J = 9.6 Hz, 1H), 8.15(s, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 7.27-7.14(m, 2H), 5.61-5.46 (m, 1H), 2.13-2.05 (m, 2H), 1.93- 392.2 1.87 (m, 2H),1.80- 1.72 (m, 2H), 1.52-1.41 (m, 2H), 1.13 (s, ₆ h). 154 10- 100 10-100 10- 100

2-(6- (((1R,5S,7r)-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)(methyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO- d₆) δ 13.86 (s, 1H), 13.00 (s, 1H), 8.23- 8.18 (m, ₃ h),7.82 (d, J = 8.3 Hz, 1H), 7.32-7.04 (m, ₃ h), 5.81 (s, 1H), 3.81 (d, J =10.8 Hz, 2H), 3.73 (d, J = 10.8 Hz, 2H), 2.94 (d, J = 9.4 Hz, 4H), 2.31(s, 1H), 393.2 2.06-1.91 (m, 2H), 1.77-1.72 (m, 2H). 155 >1000 >1000>1000

2-(6- (((1R,5S,7s)-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)(methyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO-d₆) δ 13.90 (s, 1H), 12.98 (s, 1H), 8.27- 8.21 (m, 2H),7.98 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 10.0 Hz, 1H),7.27-7.10 (m, 2H), 4.75 (s, 1H), 3.57- 3.51 (m, 4H), 3.09-2.94 (m, 5H),2.58 (s, 1H), 393.2 2.00-1.85 (m, 2H), 1.77-1.72 (m, 2H). 156 10- 100

2-(6- (((1R,5S,7r)- 1,5-dimethyl-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)(methyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- ¹H NMR (500 MHz,DMSO-d₆) δ 13.86 (s, 1H), 12.97 (s, 1H), 8.26 (s, 1H), 8.21 (d, J = 10.1Hz, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.27-7.08 (m, ₃ h),5.90- 5.82 (m, 1H), 3.70 (d, J = 10.8 Hz, 2H), 3.15 (d, J = 8.7 Hz 2H)2.91 (s, 421.3 yl)phenol ₃ h), 1.90-1.86 (m, 1H), 1.72-1.68 (m, 2H),1.53- 1.50 (m, 2H), 0.91 (s, ₆ h). 157 >1000

2-(6- (((1R,5S,7s)- 1,5-dimethyl-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)(methyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- ¹H NMR (500 MHz,DMSO-d₆) δ 13.88 (s, 1H), 12.98 (s, 1H), 8.22 (d, J = 10.1 Hz, 1H), 7.98(s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.44 (J = 9.9 Hz, 1H), 7.29-7.05 (m,2H), 4.65-4.61 (m, 1H), 3.36 (d, J = 10.2 Hz, 2H), 2.99 (s, ₃ h), 421.3yl)phenol 2.97 (d, J = 10.2 Hz, 2H), 1.72-1.76 (m 2H), 1.45-1.41 (m,2H), 0.96 (s, ₆ h). 158 >1000 >1000 >1000

2-(6- (((1R,5S,7s)-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)oxy)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO- d₆): δ 13.32 (s, 1H), 13.02 (s, 1H), 8.44 (d, J = 9.6 Hz, 1H),8.14 (s, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 9.5 Hz, 1H),7.27-7.11 (m, 2H), 5.47-5.43 (m, 1H), 3.58-3.53 (m, 4H), 3.02 380.2 (d,J = 9.0 Hz, 2H), 2.43 (s, 2H), 2.37 (s, 1H), 1.76-1.64 (m, 2H). 159 501-1000 251- 500 501- 1000

2-(6- (((1R,5S,7r)-3- oxa-9- azabicyclo[3.3.1] nonan-7-yl)oxy)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO- d₆): δ 13.29 (s, 1H), 13.03 (s, 1H), 8.44 (d, J = 9.4 Hz, 1H),8.15 (s, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 9.4 Hz, 1H),7.30-7.15 (m, 2H), 6.27 (s, 1H), 3.73- 3.66 (m, 4H), 3.00 (s, 380.2 2H),2.42-2.25 (m, ₃ h), 1.86-1.81(m, 2H). 160 <10 <10 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ13.82 (s, 1H), 12.98 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H), 8.12 (s, 2H),7.83 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 9.9 Hz 1H) 7.21 (d, J = 1.8 Hz,1H), 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 5.71- 5.56 (m, 1H), 3.21-3.13 391.2(m, 2H), 2.92 (s, ₃ h), 2.05-1.91 (m, ₃ h), 1.85- 1.75 (m, 2H), 1.74-1.59 (m, 5H). 161 <10 <10 <10

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-4-fluoro-5- (1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.48 (s, 1H), 13.14 (s, 1H), 8.24 (d, J = 10.0 Hz, 1H), 8.11(s, 2H), 7.84 (d, J = 12.6 Hz 1H) 7.41 (d, J = 9.8 Hz, 1H), 7.30 (d, J =7.0 Hz, 1H), 5.06- 4.95 (m, 1H), 3.87 (s, 2H), 2.97 (s, ₃ h), 2.09-395.2 1.84 (m, ₆ h), 1.74-1.64 (m, 2H). 162 251- 500

6-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)quinolin-7-ol ¹H NMR (400 MHz, Methanol-d₄) δ 8.73- 8.67(m, 1H), 8.31-8.24 (m, 2H), 8.18 (d, J = 9.6 Hz, 1H), 7.39 (s, 1H),7.34-7.29 (m, 1H), 7.26 (d, J = 9.8 Hz, 1H), 5.18- 5.04 (m, 1H), 3.73-3.64 (m, 2H), 2.99 (s, ₃ h), 2.03-1.91 (m, ₆ h), 362.2 1.75-1.68 (m,2H). 163 101- 250

3-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-7- methoxynaph- ¹H NMR (500 MHz, DMSO-d₆) δ 13.30 (s,1H), 8.44 (s, 1H), 8.35 (d, J = 9.9 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H),7.48 (d, J = 9.9 Hz, 1H), 7.20 (s, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.96(dd, J = 391.1 thalen-2-ol 8.9, 2.4 Hz, 1H), 5.12- 5.08 (m, 1H),4.13-4.09 (m, 2H), 3.86 (s, ₃ h), 3.01 (s, ₃ h), 2.25-3.21 (m, 2H),2.10-2.05 (m, 4H), 1.81-1.77 (m, 2H). 164 251- 500 10- 100 10- 100

6-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-hydroxy- 3- methylbenzo[d] ¹H NMR (500 MHz, DMSO-d₆)δ 14.25 (s, 1H), 8.22 (d, J = 10.1 Hz, 1H), 7.92 (s, 1H), 7.41 (d, J =10.0 Hz 1H), 6.86 (s, 1H), 5.00- 4.88 (m, 1H), 3.77 (s, 2H), 3.41 (s, ₃h), 2.94 (s, ₃ h), 2.02-1.82 (m, ₆ h), 382.2 oxazol-2(3H)- 1.69-1.59 (m,2H). one 165 10- 100

3-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-7- (fluoromethoxy) ¹H NMR (500 MHz, DMSO-d₆) δ 13.31(s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.36 (d, J = 9.8 Hz, 1H), 7.90 (d,J = 8.8 Hz, 1H), 7.49 (d, J = 9.7 Hz, 1H), 7.38 (s, 1H), 7.27 (s, 1H),7.11 (d, J = 409.1 naphthalen-2- 8.6 Hz, 1H), 5.98 (d, J = ol 54.3 Hz,2H), 5.12-5.08 (m, 1H), 4.15-4.11 (m, 2H), 2.99 (s, ₃ h), 2.26- 1.96 (m,₆ h), 1.83-1.80 (m, 2H). 166 501- 1000

3-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-7- (difluoromethoxy) ¹H NMR (500 MHz, DMSO-d₆) δ 8.54(s, 1H), 8.34 (d, J = 9.9 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.54-7.35(m, ₃ h), 7.30 (s, 1H), 7.15-7.13 (m, 1H), 6.98 (t, J = 74.5 Hz, 1H),5.05-5.01 (m, 427.1 naphthalen-2- 1H), 3.83-3.79 (m, 2H), ol 2.99 (s, ₃h), 2.14-1.82 (m, ₆ h), 1.69-1.65 (m, 2H). 167 <10 <10 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (1H-pyrazol-4- yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 13.56 (s, 1H), 13.14 (s, 1H), 8.21 (d, J =9.9 Hz, 1H), 8.11 (s, 2H), 7.81 (d, J = 12.6 Hz, 1H), 7.35 (d, J = 9.9Hz, 1H), 7.30 (d, J = 7.0 Hz, 1H), 5.00-4.87 (m, 1H), 2.93 (s, ₃ h),1.83- 1.77 (m, 2H), 1.56-1.39 423.3 (m, ₆ h), 1.17 (s, ₆ h). 168<10 >1000 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1- ¹H NMR (500MHz, DMSO- d₆) δ 13.75 (s, 1H), 8.25 (d, J = 10.0 Hz, 1H), 7.97 (d, J =8.2 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.38 (d, J = 9.9 Hz, 1H),7.29-7.22 (m, 2H), 6.70 (s, 1H), 6.61 (d, J = 7.2 Hz, 1H), 4.94 (s, 1H),3.46 (s, ₃ h), 2.94 446.3 methylpyridin- (s, ₃ h), 1.88-1.83 (m,2(1H)-one 2H), 1.61-1.42 (m, ₆ h), 1.23 (s, ₆ h). 169 <10 >1000 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 1- ¹H NMR(500 MHz, DMSO-d₆) δ 13.50 (s, 1H), 8.25 (d, J = 10.0 Hz, 1H), 7.91 (d,J = 12.4 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 9.9 Hz, 1H),7.08 (d, J = 6.9 Hz, 1H), 6.58 (s, 1H), 6.45 (dt, J = 7.1, 1.9 Hz, 1H),5.07-4.77 (m, 464.2 methylpyridin- 1H), 3.46 (s, ₃ h), 2.94 (s,2(1H)-one ₃ h), 1.85-1.76 (m, 2H), 1.60-1.43 (m, ₆ h), 1.18 (s, ₆ h).170 <10 <10 <10

5-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 2- ¹H NMR (500MHz, DMSO-d₆) δ 8.40 (d, J = 9.9 Hz, 1H), 8.33 (s, 1H) 7.98 (d J = 8.2Hz, 1H), 7.30-7.12 (m, 4H), 4.95 (s, 1H), 3.68 (s, ₃ h), 2.92 (s, ₃ h),1.86-1.811 (m, ₃ h), 1.56-1.51 (m, ₆ h), 1.17 (s, ₆ h). 447.3methylpyridazin- 3(2H)-one 171 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(1- (methyl-d3)- 1H-pyrazol-4-yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 8.25-8.13 (m, 2H), 7.91 (d, J =0.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H),7.19-7.11 (m, 2H), 4.97-4.89 (m, 1H), 2.94 (s, ₃ h), 1.92-1.86 (m, 2H),1.70-.1.58 (m, ₆ h), 1.25 (s, ₆ h). 422.3 172 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(2- (methoxy- ¹H NMR (500 MHz,DMSO-d₆) δ 13.87 (s, 1H), 8.28-8.19 (m, 2H), 8.02-7.95 (m, 1H), 7.42-7.30 (m, 4H), 7.14 (s, 1H), 5.01-4.85 (m, 1H), 2.94 (s, ₃ h), 1.87-1.78(m, 2H), 1.57-1.44 (m, ₆ h), 1.17 (s, ₆ h). 449.3 d3)pyridin-4-yl)phenol 173 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(2- methoxypyridin- 4-yl)phenol ¹HNMR (500 MHz, DMSO- d₆) δ 13.87 (s, 1H), 8.27-8.23 (m, 2H), 8.00 (d, J =8.9 Hz, 1H), 7.48-7.25 (m, 4H), 7.14 (s, 1H), 4.94 (s, 1H), 3.90 (s, ₃h), 2.95 (s, ₃ h), 1.82 (d, J = 7.1 Hz, 2H), 1.59-1.53 (m, ₆ h), 1.18(s, ₆ h). 446.2 174 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(1- (fluoromethyl)- 1H-pyrazol-4-yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.78 (s, 1H), 9.11 (s, 1H), 8.76(s, 1H), 8.58 (s, 1H), 8.27 (d, J = 10.0 Hz, 1H), 7.92 (d, J = 8.3 Hz,1H), 7.46 (d, J = 9.9 Hz, 1H), 7.22 (d, J = 16.5 Hz, 2H), 6.17 (d, J =53.5 Hz, 2H), 5.12-5.08 (m, 1H), 2.99 (s, ₃ h), 437.2 2.18 (m, 2H),2.10-1.98 (m, 2H), 1.93-1.76 (m, 4H), 1.44 (s, ₆ h). 175 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(4-fluoro- 1H-pyrazol-1- yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 14.04 (s, 1H), 8.77 (d, J = 4.5 Hz, 1H),8.27 (d, J = 10.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 4.2Hz, 1H), 7.46 (d, J = 9.9 Hz, 1H), 7.42-7.33 (m, 2H), 5.06 (s, 1H), 3.00(s, ₃ h), 2.21-1.97 (m, 423.3 4H), 1.93-1.70 (m, 4H), 1.43 (s, ₆ h). 17610- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(4-fluoro- 1H-imidazol-1- yl)phenol¹H NMR (500 MHz, DMSO- d₆) δ 8.25 (d, J = 10.0 Hz, 1H), 8.14 (s, 1H),8.02 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 8.1, 1.7 Hz, 1H), 7.38 (d, J =9.9 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.6, 2.3 Hz, 1H),4.93 (s, 1H), 2.94 (s, ₃ h), 423.3 1.86-1.81 (m, 2H), 1.58- 1.42 (m, ₆h), 1.17 (s, ₆ h). 177 10- 100 <10 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(4-methyl- 1H-imidazol-1- yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 8.21-8.26 (m, 2H), 7.99 (d, J = 8 Hz, 1H),7.51 (s, 1H), 7.45 (d, J = 8 Hz, 1H), 7.19-7.21 (m, 2H), 5.06- 5.09 (m,1H), 2.97 (s, ₃ h), 2.16-2.21 (m, ₇ h), 1.81-2.01 (m, 4H), 1.43 (s, ₆h). 420.2 178 251- 500

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-hydroxy- 2- methylphenyl)- ¹H NMR(500 MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.21 (d, J = 10.0 Hz, 1H), 7.80 (s,1H), 7.74 (d, J = 6.9 Hz, 1H), 7.35 (d, J = 9.9 Hz, 1H), 6.77 (s, 1H),6.32 (d, J = 1.9 Hz, 1H), 6.25 (dd, J = 6.9, 2.0 Hz, 1H), 5.00- 4.89 (m,1H), 3.47 (s, ₃ 460.3 1- h), 2.93 (s, ₃ h), 2.25 (s, ₃ methylpyridin-h), 1.84-1.78 (m, 2H), 2(1H)-one 1.56-1.46 (m, ₆ h), 1.17 (s, ₆ h). 17910- 100

5-(1- (difluoromethyl)- 1H-pyrazol-4- yl)-2-(6- (((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1] octan-3- yl)methyl)amino) pyridazin-3-yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.92 (s, 1H), 8.79 (s, 1H), 8.34(s, 1H), 8.23 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.84 (t, J= 59.5 Hz, 1H), 7.38 (d, J = 10.0 Hz, 1H), 7.33-7.25 (m, 2H), 5.03-4.81(m, 1H), 2.94 (s, ₃ h), 1.90- 1.81 (m, 2H), 1.66-1.48 (m, ₆ h), 1.21 (s,₆ h). 455.3 180 101- 250 10- 100 10- 100

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8 azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1- ¹H NMR (500MHz, DMSO-d₆) δ 13.72 (s, 1H), 8.29-8.25 (m, 2H), 8.02 (d, J = 8.8 Hz,1H), 7.67 (d, J = 7.7 Hz, 2H), 7.38-7.36 (m, 1H), 7.12- 7.10 (m, 1H),4.96 (s, 1H), 3.47 (s, ₃ h), 2.95 (s, ₃ h), 1.85-1.76 (m, ₃ h),1.54-1.48 (m, ₆ h), 1.17 447.3 methylpyrimidin- (s, ₆ h). 2(1H)-one 181251- 500

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1-methyl- ¹H NMR(500 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.27 (d, J = 9.9 Hz, 1H), 8.03 (d, J= 8.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 9.9 Hz, 1H),5.05-4.87 (m, 1H), 3.43 (s, ₃ h), 2.95 (s, ₃ h), 1.91-1.75 (m, ₃ h),1.57- 1.47 (m, ₆ h), 1.17 (s, ₆ 448.2 1,3,5-triazin- h). 2(1H)-one 18210- 100 <10 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-methyl-5- (1H-pyrazol-4- yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 13.37 (s, 1H), 13.01 (s, 1H), 8.19 (d, J =9.9 Hz, 1H), 7.94 (s, 2H), 7.73 (s, 1H), 7.34 (d, J = 9.8 Hz, 1H), 7.00(s, 1H), 5.00-4.92 (m, 1H), 2.93 (s, ₃ h), 2.38 (s, ₃ h), 1.84-1.76 (m,2H), 1.60-1.42 (m, ₆ 419.2 h), 1.17 (s, ₆ h). 183 10- 100

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl) pyridin-2(1H)- ¹HNMR (500 MHz, DMSO- d₆) δ 13.81 (s, 1H), 11.88 (s, 1H), 8.24 (d, J =10.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.38(d, J = 9.8 Hz, 1H), 7.30-7.18 (m, 2H), 6.61 (s, 1H), 6.54 (d, J = 6.8Hz, 1H), 4.93 (s, 1H), 432.3 one 2.94 (s, ₃ h), 1.86-1.82 (m, 2H),1.58-1.52 (m, ₆ h), 1.18 (s, ₆ h). 184 10- 100

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)pyridin-2(1H)- ¹H NMR (500 MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.25 (d, J =10.0 Hz, 1H), 7.91 (d, J = 12.3 Hz, 1H), 7.46 (d, J = 6.7 Hz, 1H), 7.37(d, J = 9.9 Hz, 1H), 7.06 (d, J = 6.9 Hz, 1H), 6.50 (s, 1H), 6.39 (dt, J= 6.9, 1.8 Hz, 1H), 5.00-4.89 (m, 450.2 one 1H), 2.94 (s, ₃ h), 1.85-1.77 (m, 2H), 1.60-1.39 (m, ₆ h), 1.17 (s, ₆ h). 185 501- 1000

5-(2- (difluoromethoxy) pyridin-4-yl)- 2-(6- (((1R,3s,5S)-1,5-dimethyl-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino) ¹H NMR (500MHz, DMSO-d₆) δ 13.94 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.28 (d, J =10.0 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.78 (t, J = 73.5 Hz, 1H), 7.67(dd, J = 5.4, 1.6 Hz, 1H), 7.49- 7.34 (m, 4H), 4.95-4.94 482.1pyridazin-3- (m, 1H), 2.95 (s, ₃ h), yl)phenol 1.92-1.79 (m, 2H), 1.64-1.47 (m, ₆ h), 1.20 (s, ₆ h). 186 >1000 10- 100 101- 250

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(1- (trifluoromethyl)-1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.97 (s, 1H), 9.06(s, 1H), 8.54 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.94 (d, J = 8.4 Hz,1H), 7.41-7.36 (m, 2H), 7.33 (dd, J = 7.8, 1.7 Hz, 1H), 4.97 (s, 1H),2.95 (s, ₃ h), 1.98- 1.86 (m, 2H), 1.67-1.54 (m, ₆ h), 1.23 (s, ₆ h).473.2 187 10- 100 <10 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1- ¹H NMR (500MHz, DMSO-d₆) δ 13.88 (s, 1H), 8.25 (d, J = 10.0 Hz, 1H), 8.01-7.95 (m,1H), 7.90 (d, J = 7.3 Hz, 1H), 7.38 (d, J = 10.0 Hz, 1H), 7.35-7.27 (m,2H), 6.81 (d, J = 1.9 Hz, 1H),6.73 (dd, J = 7.3, 2.0 Hz, 1H), 5.98 (d, J= 464.1 (fluoromethyl) 51.1 Hz, 2H), 5.01-4.87 pyridin-2(1H)- (m, 1H),2.95 (s, ₃ h), one 1.88-1.75 (m, 2H), 1.61 1.43 (m, ₆ h), 1.18 (s, ₆ h).188 10- 100 <10 10- 100

6-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-hydroxy- ¹H NMR (500 MHz, DMSO- d₆)δ 13.35 (s, 1H), 8.63 (d, J = 4.6 Hz, 1H), 8.28 (d, J = 10.0 Hz, 1H),8.12 (s, 1H), 7.45-7.30 (m, 2H), 7.20 (s, 1H), 4.92 (s, 2H), 2.95 (s, ₃h), 2.80 (d, J = 436.3 N- 4.6 Hz, ₃ h), 1.91-1.73 methylbenzo- (m, ₃ h),1.57-1.42 (m, ₆ furan-2- h), 1.17 (s, ₆ h). carboxamide 189 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(2-fluoro- 6- methoxypyridin-4-yl)phenol ¹H NMR (500 MHz, DMSO-d6) δ 13.90 (s, 1H), 8.28 (d, J = 9.8Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.44- 7.36 (m, 3H), 7.14 (s, 2H),5.03-4.91 (m, 1H), 3.89 (s, 3H), 2.96 (s, 3H), 1.97-1.85 (m, 2H),1.72-1.50 (m, 6H), 1.23 (s, 6H). 464.3 190 101- 250

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 6-fluoropyridin-2- ol ¹H NMR (500 MHz, DMSO-d₆) δ 13.86 (s, 1H), 8.25 (d,J = 10.0 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 9.9 Hz, 1H),7.34-7.28 (m, 2H), 6.88-6.78 (m, 2H), 5.02-4.88 (m, 1H), 2.95 (s, ₃ h),1.89-1.82 (m, 2H), 1.63-1.50 (m, ₆ h), 1.20 (s, ₆ h). 450.2 191 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- methoxypyridazin- 4-yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.30 (d, J = 9.9 Hz, 1H), 8.04(d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.45 (d, J = 8.3 Hz,1H), 7.37 (d, J = 9.9 Hz, 1H), 5.00-4.87 (m, 1H), 4.08 (s, ₃ h), 2.94(s, ₃ h), 1.88-1.76 (m, ₃ h), 447.3 1.57-1.44 (m, ₆ h), 1.17 (s, ₆ h).192 10- 100 <10 <10

5-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-6-hydroxy- ¹H NMR (500 MHz, DMSO-d₆)δ 8.559-8.56 (m, 1H), 8.28 (s, 1H), 8.24 (d, J = 10.1 Hz, 1H), 7.43 (d,J = 0.7 Hz, 1H), 7.40 (d, J = 10.0 Hz, 1H), 7.11 (s, 1H), 4.94-4.90 (m,1H), 2.95 436.3 N- (s, ₃ h), 2.79 (d, J = 4.6 methylbenzo- Hz, ₃ h),1.83-1.79 (m, furan-2- 2H), 1.54-1.49 (m, J = carboxamide 15.2, 7.8 Hz,₆ h), 1.18 (d, J = 10.6 Hz, ₆ h). 193 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 1- ¹H NMR(500 MHz, DMSO-d₆) δ 13.45 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 7.95 (d, J= 12.5 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 9.8 Hz, 1H) 7.14(d J = 6.9 Hz, 1H), 6.68 (s, 1H), 6.59-6.51 (m, 1H), 5.99 (d, J = 50.8Hz, 2H), 482.2 (fluoromethyl) 5.16-4.89 (m, 1H), 2.99 pyridin-2(1H)- (s,₃ h), 2.07-1.61 (m, ₈ one h), 1.32 (s, ₆ h). 194 10- 100

6-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 3- ¹H NMR (500MHz, DMSO-d₆) δ 13.67 (s, 1H), 8.56 (s, 1H), 8.26 (d, J = 9.9 Hz, 1H),7.99 (d, J = 8.3 Hz, 1H), 7.64- 7.58 (m, 2H), 7.40 (d, J = 9.9 Hz, 1H),7.00 (s, 1H), 5.06-4.88 (m, 1H), 3.44 (s, ₃ h), 2.96 (s, ₃ h), 2.03-1.86(m, 2H), 1.82- 447.2 methylpyrimidin- 1.53 (m, ₆ h), 1.32- 4(3H)-one1.18 (m, ₆ h). 195 501- 1000

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1-methyl-1H-pyrrole-2- ¹H NMR (500 MHz, DMSO-d₆) δ 13.85 (s, 1H), 8.19 (d, J = 9.8Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.44 (d, J = 1.8 Hz,1H), 7.35 (d, J = 9.8 Hz, 1H), 7.14 (d, J = 10.3 Hz, 2H), 4.99- 4.85 (m,1H), 3.79 443.3 carbonitrile (s, 3H), 2.93 (s, 3H), 1.86-1.78 (m, 2H),1.56-1.49 (m, 6H), 1.17 (s, 6H). 196 251- 500

1-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1H-imidazole- ¹HNMR (500 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.62 (s, 1H), 8.27 (d, J = 9.3Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.48- 7.15 (m, 2H), 4.94 (s, 1H),2.94 (s, ₃ h), 1.93- 1.70 (m, 2H), 1.63-1.42 (m, ₆ h), 1.17 (s, ₆ h).430.0 4-carbonitrile 197 >1000

1-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- ¹H NMR(500 MHz, DMSO-d₆) δ 9.00 (d, J = 9.5 Hz, 1H), 8.44 (s, 1H), 8.15 (s,1H), 7.75 (d, J = 13.7 Hz, 1H), 6.90 (d, J = 9.7 Hz, 1H), 6.21 (d, J =7.1 Hz, 1H), 5.06- 4.91 (m, 1H), 2.85 (s, 448.2 1H-imidazole- 3H),1.81-1.78 (m, 4-carbonitrile 2H), 1.52-1.45 (m, 6H), 1.16 (s, 6H). 198<10

6-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 3- ¹H NMR(500 MHz, Methanol-d₄) δ 8.51 (s, 1H), 8.14 (d, J = 9.9 Hz, 1H), 7.73-7.64 (m, 2H), 7.33 (d, J = 9.8 Hz, 1H), 7.02 (s, 1H), 5.19-5.11 (m, 1H),3.59 (s, 3H), 3.03 (s, 3H), 2.08- 2.02 (m, 2H), 1.78- 465.4methylpyrimidin- 1.65 (m, 6H), 1.33 (s, 4(3H)-one 6H). 199 10- 100

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl) picolinonitrile ¹HNMR (500 MHz, DMSO-d6) δ 8.70 (d, J = 5.2 Hz, 1H), 8.61- 8.55 (m, 1H)8.29 (d, J = 1.8 Hz, 1H), 7.99- 7.92 (m, 2H), 7.14- 7.07 (m, 2H), 6.99(d, J = 8.1 Hz, 1H), 5.04- 4.89 (m, 1H), 2.89 (s, 3H), 1.83-1.78 (m,441.0 2H), 1.53-1.46 (m, 6H), 1.17 (s, 6H). 200 101- 250

1-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1H-pyrazole-4- ¹HNMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.38 (s, 1H), 8.24 (d, J = 9.9Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.57- 7.24 (m, ₃ h), 4.93 (s, 1H),2.94 (s, ₃ h), 1.88- 1.73 (m, 2H), 1.64-1.36 (m, ₆ h), 1.17 (s, ₆ h).430.0 carbonitrile 201 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(ethyl)amino) pyridazin-3- yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO-d₆) δ 13.81 (s, 1H), 12.98 (s, 1H), 8.22-7.98 (m, 3H),7.82 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 9.9 Hz, 1H), 7.23-7.15 (m, 2H),4.98-4.83 (m, 1H), 3.48-3.44 (m, 2H), 1.93-1.82 (m, 2H), 1.65-1.49 419.0(m, 6H), 1.21 (s, 6H), 1.14 (t, J = 6.9 Hz, 3H). 202 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(ethyl)amino) pyridazin-3- yl)-4-fluoro-5- (1H-pyrazol-4- yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 13.56 (s, 1H), 13.14 (s, 1H), 8.18 (d, J =9.9 Hz, 1H), 8.11 (s, 2H), 7.80, (d, J = 12.5 Hz, 1H), 7.34-7.24 (m,2H), 4.98-4.79 (m, 1H), 3.51-3.43 (m, 2H), 1.84-1.76 (m, 2H), 437.01.64-1.43 (m, 6H), 1.21-1.10 (m, 9H). 203 10- 100

1-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1H-pyrrole-3- ¹HNMR (500 MHz, DMSO-d₆) δ 14.2 (s, 1H), 8.35-8.32 (m, 1H), 8.25 (d, J =10.0 Hz, 1H) 8.01 (d J = 8.8 Hz, 1H), 7.67- 7.63 (m, 1H), 7.38 (d, J =10.0 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.27-7.20 (m, 1H), 429.2carbonitrile 6.76-6.69 (m, 1H), 4.92 (s, 1H), 2.94 (s, 3H), 1.83-1.76(m, 2H), 1.54-1.45 (m, 6H), 1.17 (s, 6H). 204 100- 500

5-(2,6- difluoropyridin- 4-yl)-2-(6- (((1R,3s,5S)- 1,5-dimethyl-8-azabicyclo[3.2.1] octan-3- yl)(methyl)amino) pyridazin-3- yl)phenol ¹HNMR (500 MHz DMSO-d₆) δ 8.32 (d, J = 9.9 Hz, 1H), 8.04 (d, J = 8.4 Hz,1H), 7.62 (s, 2H), 7.51- 7.42 (m, 2H), 7.37 (d, J = 9.9 Hz, 1H), 5.02-4.89 (m, 1H), 2.94 (s, 3H), 1.89-1.75 (m, 3H), 1.56-1.45 (m, 6H), 1.17(s, 6H). 452.2 205 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- (methoxy- ¹H NMR (500 MHz,DMSO-d₆) δ 14.00 (s, 1H), 9.35 (s, 1H), 8.40- 8.18 (m, 1H), 8.12-7.94(m, 1H), 7.66-7.23 (m, 4H), 5.09-4.81 (m, 1H), 2.95 (s, ₃ h), 1.86-1.76(m, 2H), 1.60-1.43 (m, ₆ h), 1.17 (s, ₆ h). 450.3 d3)pyridazin-4-yl)phenol 206 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (6-(methoxy- ¹H NMR (500MHz, DMSO-d₆) δ 9.21- 9.01 (m, 1H), 8.48- 8.29 (m, 1H), 8.02- 7.78 (m,1H), 7.44- 7.07 (m, 3H), 5.06- 4.79 (m, 1H), 2.93 (s, 3H), 1.87-1.77 (m,2H), 1.58-1.43 468.2 d3)pyridazin-4- (m, 6H), 1.17 (s, yl)phenol 6H).207 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(2-fluoro- 6-(methoxy-d3)pyridin-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.88 (s, 1H), 8.29(d, J = 9.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.45- 7.36 (m, 3H), 7.13(s, 2H), 5.06-4.95 (m, 1H), 2.97 (s, 3H) 2.04- 1.90 (m, 2H), 1.80- 1.52(m, 6H), 1.28 (s, 6H). 467.3 208 >1000

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (2-fluoro-6- (methoxy-d3)pyridin-4- ¹H NMR (500 MHz, DMSO-d₆) δ 13.61 (s, 1H), 8.28 (d, J =10.0 Hz, 1H), 7.96 (d, J = 12.3 Hz, 1H), 7.38 (d, J = 9.8 Hz, 1H), 7.20(d, J = 6.9 Hz, 1H), 6.99 (d, J = 6.8 Hz, 2H), 5.00- 4.90 (m, 1H), 2.95(s, 3H), 1.84-1.78 (m, 2H), 1.54-1.47 485.3 yl)phenol (m, 6H), 1.17 (s,6H). 209 >1000

4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-3′-methoxy- [1,1′-biphenyl]- 3-ol ¹HNMR (500 MHz, DMSO-d₆) δ 13.80 (s, 1H), 8.22 (d, J = 9.9 Hz, 1H), 7.94(d, J = 8.8 Hz, 1H), 7.43-7.33 (m, 2H), 7.31-7.20 (m, 4H), 6.99-6.93 (m,1H), 5.04-4.76 (m, 1H), 3.84 (s, 3H), 2.94 445.2 (s, 3H), 1.86-1.79 (m,2H), 1.56-1.45 (m, 6H), 1.17 (s, 6H). 210 251- 500

4-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4′-fluoro-3′- methoxy-[1,1′-biphenyl]-3-ol ¹H NMR (500 MHz, DMSO-d₆) δ 13.95- 13.18 (m, 1H), 8.24(d, J = 9.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H),7.36 (d, J = 9.5 Hz, 1H), 7.37- 7.15 (m, 4H), 4.99- 4.93 (m, 1H), 3.95(s, 463.2 3H), 2.94 (s, 3H), 1.92- 1.66 (m, 3H), 1.62- 1.29 (m, 6H),1.17 (s, 6H). 211 251- 500

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(5- methoxypyridin- 3-yl)phenol ¹HNMR (500 MHz, DMSO-d₆) δ 13.90 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.30(d, J = 2.7 Hz, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.99 (d, J = 8.3 Hz,1H), 7.67 (s, 1H), 7.42-7.29 (m, ₃ h), 5.02- 4.87 (m, 1H), 3.93 (s, ₃h), 2.94 (s, ₃ h), 1.86- 446.3 1.75 (m, 2H), 1.58-1.45 (m, ₆ h), 1.17(s, ₆ h). 212

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6-fluoro- 5- methoxypyridin- ¹HNMR (500 MHz, DMSO-d₆) δ 13.95 1H), 8.26 (d, J = 9.9 Hz, 1H), 8.08 (s,1H), 7.99 (d, J = 8.3 Hz, 1H), 7.95-7.91 (m, 1H), 7.40-7.30 (m, 3H),5.02-4.80 (m, 1H), 4.00 (s, 3H), 2.94 (s, 3H), 1.85-1.76 464.33-yl)phenol (m, 2H), 1.56-1.48 (m, 6H), 1.17 (s, 6H). 213 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (6- methoxypyridazin- ¹HNMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.32 (d, J = 9.8 Hz, 1H), 7.97(d, J = 12.3 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 9.8 Hz, 1H), 7.26 (d, J= 6.8 Hz, 1H), 5.06- 4.87 (m, 1H), 4.09 (s, 3H), 2.94 (s, 3H), 1.85-465.4 4-yl)phenol 1.75 (m, 2H), 1.56- 1.45 (m, 6H), 1.17 (s, 6H). 214

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl- d3)amino)pyrid- azin-3-yl)-4- fluoro-5-(1H- pyrazol-4-yl)phenol ¹H NMR (500 MHz DMSO-d₆) δ 13.56 (s,, 1H), 13.14 (s, 1H), 8.21(d, J = 10.0 Hz, 1H), 8.11 (s, 2H), 7.82 (d, J = 12.6 Hz, 1H), 7.35 (d,J = 9.8 Hz, 1H), 7.30 (d, J = 6.9 Hz, 1H), 5.02-4.88 (m, 1H), 1.86-1.77(m, 2H), 1.57-1.45 (m, 6H), 1.18 (s, 6H). 426.1 215

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- methoxypyrimi- din-4-yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.54 (s, 1H), 7.94 (d, J = 7.9Hz, 1H), 7.47 (s, 1H), 7.36 (s, 2H), 7.16 (d, 1H), 5.02-4.90 (m, 1H),3.96 (s, 3H), 2.90 (s, 3H), 1.92-1.69 (m, 3H), 1.60-1.36 (m, 447.3 6H),1.12 (s, 6H). 216

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (6- methoxypyrimi- ¹H NMR(500 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.92 (s, 1H), 8.29 (d, J = 9.8 Hz,1H) 7.96 (d, J = 13.0 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.40 (d, J =9.9 Hz, 1H), 7.30 (s, 1H), 5.12-4.90 (m, 1H), 3.99 (s, 3H), 2.97 485.1din-4-yl)phenol (s, 3H), 2.02-1.88 (m, 2H), 1.84-1.55 (m, 6H), 1.28 (s,6H). 217 10- 100 <10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- imidazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆)δ 8.35 (s, 1H), 8.25 (d, J = 9.9 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.83(d, J = 1.5 Hz, 1H), 7.36 (d, J = 9.8 Hz 1H), 7.30 (s, 1H), 7.21 (d, J =9.6 Hz, 1H), 7.10 (s, 1H), 4.98-4.83 (m, 1H), 3.48 (s, 2H), 2.92 377.2(s, ₃ h), 1.84-1.68 (m, ₆ h), 1.56-1.47 (m, 2H). 218 10- 100 <10 <10

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(4-methyl- 1H-imidazol-1- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 14.23 (s, 1H), 8.25-8.20 (m, 2H), 7.98 (d, J = 8.6 Hz, 1H),7.52 (s, 1H), 7.38 (d, J = 10.0 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.18(dd, J = 8.5, 2.5 Hz, 1H), 4.98-4.79 (m, 1H), 3.53- 3.45 (m, 2H), 2.93(s, ₃ h), 2.16 (s, ₃ h), 1.85- 391.1 1.70 (m, ₆ h), 1.59-1.48 (m, 2H).219 >1000 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(5-methyl- 1,3,4-oxadiazol- 2-yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 13.68 (s, 1H), 9.09 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H),8.12 (d, J = 8.4 Hz, 1H), 7.54- 7.44 (m, ₃ h), 5.13- 4.94 (m, 1H),4.14-4.05 (m, 2H), 3.02 (s, ₃ h), 2.60 (s, ₃ h), 2.33-2.21 (m, 2H),2.09-1.99 (m, 393.2 4H), 1.80-1.72 (m, 2H). 220 10- 100 <10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- pyrazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ14.11 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 10.0 Hz, 1H), 8.0(d, J = 10.0 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.47-7.40 (m, 2H), 7.38(d, J = 9.9 Hz, 1H), 6.62-6.51 (m, 1H), 4.92-4.88 (m, 1H), 3.50 377.4(s, 2H), 2.95 (s, ₃ h), 1.98- 1.69 (m, ₆ h), 1.56-1.52 (m, 2H). 221 101-250 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(4-methyl- 1H-pyrazol-1- yl)phenol ¹H NMR (500 MHz,DMSO) δ 8.33 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 9.4 Hz,1H), 7.58 (s, 1H), 7.38- 7.32 (m, ₃ h), 4.94-4.83 (m, 1H), 3.48 (s, 2H),2.93 (s, ₃ h), 2.10 (s, ₃ h), 1.83-1.69 (m, ₆ h), 1.56- 1.48 (m, 2H).391.3 222 10- 100 <10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(3-methyl- 1H-pyrazol-1- yl)phenol ¹H NMR (500 MHz,DMSO) δ 8.44 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.95 (d, J= 8.8 Hz, 1H), 7.41- 7.32 (m, ₃ h), 6.34 (d, J = 2.3 Hz, 1H), 4.99-4.83(m, 1H), 3.50 (s, 2H), 2.93 (s, ₃ h), 2.28 (s, ₃ h), 1.85-1.69 (m, ₆ h),1.53 391.3 (m, 2H). 223 10- 100 <10 <10

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2H-1,2,3- triazol-2- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.13 (d, J = 9.9 Hz, 1H), 7.97- 7.89 (m, ₃ h), 7.70-7.63(m, 2H) 7.32 (d, J = 9.9 Hz, 1H), 5.21-5.00 (m, 1H), 3.79-3.57 (m, 2H),3.01 (s, ₃ h), 2.11-1.89 (m, ₆ h), 1.80-1.67 (m, 2H). 378.3 224 101- 250<10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H-1,2,3- triazol-1- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 8.91 (s, 1H), 8.26 (d, J = 9.9 Hz, 1H), 8.10 (d, J = 8.5 Hz,1H), 7.99 (s, 1H), 7.55- 7.48 (m, 2H), 7.43-7.35 (m, 1H), 5.00-4.86 (m,1H), 3.50 (s, 2H), 2.95 (s, ₃ h), 1.85-1.70 (m, ₆ h), 1.61-1.48 (m, 2H).378.2 225 10- 100 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(4-methyl- 1H-1,2,3- triazol-1- yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.26 (d, J = 9.9 Hz, 1H), 8.07 (d, J = 8.4Hz, 1H), 7.45-7.37 (m, ₃ h), 4.93 (s, 2H), 3.48 (s, 2H), 2.94 (s, ₃ h),2.33 (s, ₃ h), 1.84-1.66 (m, ₆ h), 1.56-1.52 (m, 2H). 392.2 226 101- 25010- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H-1,2,3- triazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.19- 8.12 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.49- 7.41(m, 2H), 7.34 (d J = 9.9 Hz, 1H), 5.20- 5.13 (m, 1H), 3.84 (s, 2H), 3.02(s, ₃ h), 2.12- 2.01 (m, ₆ h), 1.84-1.77 (m, 2H). 378.3 227 >1000 >1000>1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- tetrazol-5- yl)phenol ¹H NMR (500 MHz, DMSO-d₆)δ 13.44 (s, 1H), 8.23 (d, J = 9.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H),7.55 (dd, J = 8.2, 1.5 Hz 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.44 (d, J =9.8 Hz, 1H), 5.05-5.01 (m, 1H), 4.09-4.05 (m, 2H), 2.96 (s, ₃ h), 2.13-379.3 1.98 (m, ₆ h), 1.81-1.77 (m, 2H). 228 10- 100 <10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2- methyloxazol- 5-yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.13 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.43(s, 1H), 7.33 (d, J = 9.8 Hz, 1H), 7.30-7.24 (m, 2H), 5.15-5.07 (m, 1H),3.72 (s, 2H), 3.02 (s, ₃ h), 2.56 (s, ₃ h), 2.05-1.95 (m, ₆ h),1.77-1.71 (m, 2H). 392.2 229 >1000 >1000 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(3- methylisoxazol- 5-yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 7.41 (d, J = 8.5 Hz, 1H), 7.03 (m, 4H), 6.15 (s, 1H), 5.00-4.86 (m, 1H), 3.48 (s, 2H), 2.87 (s, ₃ h), 2.19 (s, ₃ h), 1.82-1.65 (m,₆ h), 1.57-1.42 (m, 2H). 392.3 230 >1000 101- 250 501- 1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2-methyl- 1H-imidazol-1- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.99 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 8.03 (d, J = 8.3Hz, 1H), 7.43 (d, J = 9.9 Hz, 1H), 7.34 (s, 1H), 7.04-6.97 (m, 2H), 6.92(d, J = 1.4 Hz, 1H), 4.98- 4.96 (m, 1H), 3.78 (s, 2H), 2.98 (s, ₃ h),2.36 (s, 391.2 ₃ h), 2.09-1.96 (m, 2H), 1.89 (s, 4H), 1.68-1.59 (m, 2H).231 >1000 251- 500 501- 1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2,4- dimethyl-1H- imidazol-1- yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 14.04 (s, 1H), 8.23 (d, J = 10.0 Hz, 1H), 7.99 (d, J =8.6 Hz, 1H), 7.39 (d, J = 9.9 Hz, 1H), 7.02 (d, J = 1.3 Hz, 1H),6.98-6.92 (m, 2H), 4.97-4.82 (m, 1H), 3.54 (s, 2H), 2.94 (s, ₃ h), 2.31(s, ₃ h), 2.09 (s, ₃ h), 1.86-1.70 (m, ₆ h), 1.59- 405.3 1.50 (m, 2H).232 >1000 101- 250 501- 1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(5- (trifluoromethyl)- 1,3,4- oxadiazol-2- ¹H NMR(500 MHz, Methanol-d₄) δ 8.26 (d, J = 9.9 Hz, 1H), 8.05 (d, J = 8.1 Hz,1H), 7.74- 7.66 (m, 2H), 7.41 (d, J = 9.9 Hz, 1H), 5.57- 5.36 (m, 1H),4.23-4.21 (m, 2H), 3.08 (s, ₃ h), 2.36-2.16 (m, ₆ h), 2.01- 1.98 (m,2H). 447.2 yl)phenol 233 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(5-methyl- 1H-tetrazol-1- yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 9.01 (s, 1H), 8.88 (s, 1H), 8.34 (d, J = 9.9 Hz, 1H), 8.11(d, J = 8.5 Hz, 1H), 7.63 (d, J = 9.9 Hz, 1H), 7.29- 7.24 (m, 2H), 5.19-4.84 (m, 1H), 4.33-3.98 (m, 2H), 3.02 (s, ₃ h), 2.49 (s, ₃ h), 2.28-1.81393.3 (m, ₈ h). 234 10- 100 10- 100 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(5-methyl- 2H-tetrazol-2- yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 13.94 (s, 1H), 8.93 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 8.18(d, J = 8.6 Hz, 1H), 7.69- 7.52 (m, 2H), 7.49 (d, J = 10.0 Hz, 1H),5.14- 4.99 (m, 1H), 4.10 (s, 2H), 3.01 (s, ₃ h), 2.60 (s, ₃ h),2.30-2.14 (m, 2H), 2.14-1.94 (m, 4H), 1.85- 393.2 1.67 (m, 2H). 235>1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(4H-1,2,4- triazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 14.27 (s, 1H), 9.23 (s, 2H), 9.01- 8.53 (m, 1H), 8.33 (d, J =10.0 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 9.8 Hz, 1H), 7.38(s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 5.06-5.06 (m, 1H), 4.11 (s, 2H), 2.99(s, ₃ h), 378.2 2.23-1.95 (m, ₆ h), 1.85- 1.79 (m, 2H). 236 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(6- methylpyridin- 3-yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 13.86 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 10.0Hz, 1H), 8.06-7.93 (m, 2H), 7.40-7.23 (m, 4H), 5.03-4.77 (m, 1H), 3.50(s, 2H), 3.31 (s, ₃ h), 2.94 (s, ₃ h), 1.85-1.67 (m, ₆ h), 1.58-1.47 (m,2H). 402.2 237 501- 1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2- methylpyrimidin- 5-yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 13.87 (s, 1H), 9.07 (s, 2H), 8.30 (d, J = 9.9 Hz, 1H), 8.04(d, J = 8.3 Hz, 1H), 7.45 (d, J = 10.0 Hz, 1H), 7.40-7.32 (m, 2H), 5.10-4.93 (m, 1H), 3.93 (s, 2H), 2.99 (s, ₃ h), 2.67 (s, ₃ h), 2.18-2.06 (m,2H), 2.03-1.90 (m, 4H), 1.75- 403.1 1.67 (m, 2H). 238 10- 100 <10 10-100

5-(4-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 2- methylpyridazin- 3(2H)-one ¹H NMR(400 MHz, DMSO-d₆) δ 13.95 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.27 (d, J= 9.8 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.44-7.34 (m, ₃ h), 7.26 (d, J= 2.2 Hz, 1H), 4.99-4.84 (m, 1H), 3.69 (s, ₃ h), 3.50 (s, 2H), 2.94 (s,₃ h), 1.84-1.71 (m, ₆ h), 1.57-1.50 (m, 2H). 419.2 239 251- 500 <10 <10

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)aminopyridazin-3- yl)-5-(6- methylpyridazin- 3-yl)phenol ¹H NMR (400 MHz,DMSO-d₆) δ 13.80 (s, 1H), 8.27 (d, J = 10.0 Hz, 1H), 8.18 (d, J = 8.8Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.77-7.69 (m, 2H), 7.66 (d, J = 8.8Hz, 1H), 7.40 (d, J = 9.9 Hz, 1H), 5.02-4.89 (m, 1H), 3.56 (s, 2H), 2.95(s, ₃ h), 403.2 2.67 (s, ₃ h), 1.93-1.65 (m, ₆ h), 1.60-1.50 (m, 2H).240 10- 100 <10 <10

4-(4-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1- methylpyridin- 2(1H)-one ¹H NMR(400 MHz, DMSO-d₆) δ 13.84 (s, 1H), 8.24 (d, J = 10.0 Hz, 1H), 7.97 (d,J = 8.2 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 10.0 Hz, 1H),7.29-7.21 (m, 2H), 6.70 (d, J = 2.1 Hz, 1H), 6.64-6.59 (m, 1H),4.99-4.82 (m, 1H), 3.52-3.43 (m, 5H), 2.94 418.1 (s, ₃ h), 1.84-1.68 (m,₆ h), 1.58-1.49 (m, 2H). 241 101- 250 <10 10- 100

5-(4-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1- methylpyridin- ¹H NMR (400 MHz,DMSO-d₆) δ 13.91 (s, 1H), 8.32-8.15 (m, 2H), 7.97-7.82 (m, 2H), 7.36 (d,J = 9.9 Hz, 1H), 7.20- 7.11 (m, 2H), 6.48 (d, J = 9.5 Hz, 1H), 5.04-4.73 (m, 1H), 3.52 (s, ₃ h), 3.48 (s, 2H), 2.93 (s, ₃ h), 1.86-1.65 (m,₆ h), 418.2 2(1H)-one 1.59-1.47 (m, 2H). 242 251- 500 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(4- (trifluoromethyl)- 1H-imidazol- 1-yl)phenol ¹HNMR (500 MHz, DMSO-d₆) δ 14.27 (s, 1H), 8.57 (d, J = 14.3 Hz, 2H), 8.34(d J = 10.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 10.0 Hz,1H), 7.39 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H),5.08-5.04(m, 1H), 4.12- 4.08 (m, 2H), 3.01 (s, ₃ h), 2.28-2.24 (m, 2H),445.1 2.08-2.04 (m, 4H), 1.80- 1.76 (m, 2H). 243 10- 100 <10 10- 100

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H-1,2,4- triazol-1- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 14.10 (s, 1H), 9.39 (s, 1H), 9.33- 8.89 (m, 1H), 8.36-8.19(m, 2H), 8.10 (d, J = 8.7 Hz, 1H), 7.49-7.45 (m, 2H), 5.06 (s, 1H), 4.10(s, 2H), 3.01 (s, ₃ h), 2.29-2.22 (m, 2H), 2.12- 1.94 (m, 4H), 1.85-1.77378.2 (m, 2H). 244 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(3-methyl- 1H-1,2,4- triazol-1- yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.23 (d, J = 9.9 Hz, 1H), 8.03 (d, J = 8.6Hz, 1H), 7.48-7.27 (m, ₃ h), 4.91 (s, 1H), 3.50 (s, 2H), 2.94 (s, ₃ h),2.37 (s, ₃ h), 1.89-1.64 (m, ₆ h), 1.55-1.52 (m, 2H). 392.3 245 501-1000 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- imidazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (d,J = 9.5 Hz, 1H), 8.39 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.86 (s, 1H),7.42 (d, J = 9.4 Hz, 1H), 7.36- 7.27 (m, 2H), 7.12 (s, 1H), 5.56-5.46(m, 1H), 364.2 3.58-3.56 (m, 2H), 2.24- 2.13 (m, 2H), 1.83- 1.71 (m,4H), 1.67-1.58 (m, 2H). 246 251- 500 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(4- methyl-1H- imidazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ8.46 (d, J = 9.6 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 8.7 Hz,1H), 7.54 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.30-7.20 (m, 2H),5.54-5.43 (m, 1H), 3.55- 3.48 (m, 2H), 2.20- 2.11 (m, 5H), 1.75-1.55378.1 (m, ₆ h). 247 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(5- methyl-1,3,4- oxadiazol-2- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 8.40 (d, J = 9.5 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.56-7.53(m, 2H), 7.38 (d, J = 9.4 Hz, 1H), 5.70-5.37 (m, 1H), 3.63-3.60 (m, 2H),2.60 (s, ₃ h), 2.23-2.19 (m, 2H), 1.77-1.74 (m, 380.2 4H), 1.68-1.63 (m,2H). 248 501- 1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- pyrazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (d, J= 2.5 Hz, 1H), 8.44 (d, J = 9.5 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.78(d, J = 1.5 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.7, 2.2Hz, 1H), 7.41 364.1 (d, J = 9.5 Hz, 1H), 6.66- 6.50 (m, 1H), 5.57-5.49(m, 1H), 3.69 (s, 2H), 2.27-2.21 (m, 2H), 1.85-1.63 (m, ₆ h). 249501- 1000 101- 250 251- 500

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(4- methyl-1H- pyrazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ8.45 (d, J = 9.5 Hz, 1H), 8.32 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.58(s, 1H), 7.39 (s, 1H), 7.33 (d, J = 9.4 Hz, 2H), 5.54-5.44 (m, 1H), 3.50(s, 2H), 2.19- 2.12 (m, 2H), 2.10 (s, ₃ h), 1.78-1.66 (m, 4H), 378.31.61-1.57 (m, 2H). 250 501- 1000 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(3- methyl-1H- pyrazol-1- ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d, J= 2.4 Hz, 1H), 8.44-8.39 (m, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.44 (d, J =2.2 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 9.5 Hz, 1H), 6.36(d, J = 2.4 378.3 yl)phenol Hz, 1H), 5.54-5.44 (m, 1H), 3.50 (s, 2H),2.28 (s, ₃ h), 2.19-2.11 (m, 2H), 1.76-1.66 (m, 4H), 1.64-1.54 (m, 2H).251 251- 500 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(2H- 1,2,3-triazol-2- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ8.25 (d, J = 9.5 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.85 (s, 2H),7.64-7.57 (m, 2H), 7.23-7.19 (m, 1H), 5.69- 5.41 (m, 1H), 4.11 (s, 2H),2.64-2.40 (m, 2H), 2.21-2.03 (m, 4H), 365.1 1.96-1.89 (m, 2H). 252 501-1000 101- 250 251- 500

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- 1,2,3-triazol-1- yl)phenol ¹H NMR (500 MHz, Methanol-d₄) δ8.63 (d, J = 1.1 Hz, 1H), 8.38 (d, J = 9.5 Hz, 1H), 8.08 (d, J = 8.6 Hz,1H), 7.94 (d, J = 1.1 Hz, 1H), 7.62- 7.42 (m, 2H), 7.31 (d, J = 9.5 Hz,1H), 5.76- 365.2 5.53 (m, 1H), 3.80 (s, 2H), 2.53-2.29 (m, 2H),2.09-1.95 (m, 4H), 1.86-1.81 (m, 2H). 253 501- 1000 251- 500 251- 500

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- 1,2,3-triazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ8.45-8.42 (m, 2H), 8.02 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H),7.47 (dd, J = 8.2, 1.5 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 5.50 (m, 1H),3.53 (s, 2H), 2.17 (m, 2H), 1.73 (m, 4H), 385.2 1.61 (m, 2H).254 >1000 >1000 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(1H- tetrazol-5- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 12.51 (s,1H), 8.53 (s, 1H), 8.42 (d, J = 9.6 Hz, 1H), 7.94 (d, J = 8.1 Hz 1H),7.63- 7.56 (m, 2H), 7.40 (d, J = 9.4 Hz, 1H), 5.67- 5.48 (m, 1H),4.14-4.09 (m, 2H), 2.45-2.41 (m, 366.1 2H), 2.10-1.86 (m, ₆ h). 255 501-1000 101- 250 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(2- methyloxazol- 5-yl)phenol ¹H NMR (500 MHz, DMSO) δ 8.44 (d,J = 9.5 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.36 (d, J =9.4 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.63- 5.34 (m, 1H),3.52-3.49 (m, 2H), 2.50 (s, ₃ 378.9 h),2.18-2.12 (m, 2H), 1.79-1.52 (m,₆ h). 256 >1000 >1000 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(3- methylisoxazol- 5-yl)phenol ¹H NMR (400 MHz, DMSO-d₆) δ 7.44(d, J = 8.4 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.15-6.97 (m, ₃ h), 6.18(s, 1H), 5.57-5.40 (m, 1H), 3.50 (s, 2H), 2.23-2.08 (m, 5H), 1.76-1.64(m, 4H), 1.60-1.55 (m, 2H). 379.1 257 >1000

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(5- methyl-1H- tetrazol-1- yl)phenol ¹H NMR (400 MHz, DMSO-d₆) δ12.88 (s, 1H), 8.88 (s, 1H), 8.46 (d, J = 9.5 Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.50- 7.28 (m, ₃ h), 5.62-5.58 (m, 1H), 4.15 (s, 2H), 2.63 (s,₃ h), 2.48-2.92 (m, ₈ h). 380.2 258 251- 500 10- 100 101- 250

2-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)oxy)pyridazin-3-yl)-5-(5- methyl-2H- tetrazol-2- yl)phenol ¹H NMR (400 MHz, DMSO-d₆) δ12.65 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 9.5 Hz, 1H), 8.17 (d, J = 8.6Hz, 1H), 7.77- 7.60 (m, 2H), 7.45 (d, J = 9.4 Hz, 1H), 5.68- 5.44 (m,1H), 4.13 (s, 2H), 2.61 (s, ₃ h), 2.48- 380.2 2.39 (m, 2H), 2.08-2.00(m, ₆ h). 259 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 1- ¹H NMR (500MHz, DMSO-d₆) δ 13.8 (s, 1H), 8.21 (d, J = 9.9 Hz, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.36-7.24 (m, ₃ h), 6.78-6.63 (m,2H), 5.77 (s, 1H), 3.48 (s, ₃ h), 2.88 (s, ₃ h), 2.08-2.01 (m, 1H),1.67-0.99 (m, 15H). 460.3 methylpyridin- 2(1H)-one 260 <10

5-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- 2- ¹H NMR (500MHz, DMSO-d₆) δ 13.95 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.28 (d, J =10.0 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.48-7.35 (m, 2H), 7.30 (d, J =9.7 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 5.85-5.63 (m, 1H), 3.69 (s, ₃ h),2.89 (s, ₃ h), 461.2 methylpyridazin- 1.72-1.55 (m, 4H), 1.51- 3(2H)-one1.37 (m, 2H), 1.37- 1.17 (m, 4H), 1.04 (s, ₆ h). 261 10- 100

5-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-6-hydroxy- ¹H NMR (500 MHz,Methanol-d₄) δ 8.22 (d, J = 9.9 Hz, 1H), 8.16 (s, 1H), 7.46 (s, 1H),7.36 (d, J = 9.8 Hz, 1H), 7.11 (s, 1H), 6.13-6.00 (m, 1H), 3.01 (s, ₃h), 2.97 (s, ₃ h), 2.49-2.36 (m, 1H), 450.0 N- 2.17-2.08 (m, 4H), 2.05-methylbenzo- 1.77 (m, 5H), 1.49 (s, ₆ furan-2- h). carboxamide 262 101-250

2-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)oxy)pyridazin- 3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 8.77-8.58 (m, 1H), 8.48 (d, J = 9.7 Hz, 1H),8.30 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 9.6Hz, 1H), 7.25 (d, J = 10.2 Hz, 1H), 6.16-6.01 (m, 1H), 2.61-2.52 (m,2H), 406.2 2.02-1.86 (m, ₃ h), 1.83- 1.71 (m, ₃ h), 1.69- 1.57 (m, 2H),1.37 (s, ₆ h). 263 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)oxy)pyridazin- 3-yl)-4- fluoro-5-(1H- pyrazol-4- ¹H NMR (500 MHz,DMSO-d₆) δ 13.20 (s, 1H), 8.74-8.59 (m, 2H), 8.49 (d, J = 9.6 Hz, 1H),8.25 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 12.4 Hz, 1H), 7.45 (d, J = 9.6Hz, 1H), 7.36 (d, J = 6.9 Hz, 424.3 yl)phenol 1H),6.14-5.96 (m, 0H),1.98-1.88 (m, 3H), 1.80-1.72 (m, 3H), 1.68-1.58 (m, 2H), 1.37 (s, 6H).264

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 1- ¹H NMR(500 MHz, DMSO-d₆) δ 13.52 (s, 1H), 8.27 (d, J = 10.0 Hz, 1H), 7.93 (d,J = 12.5 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 9.9 Hz, 1H),7.13 (d, J = 6.9 Hz, 1H), 6.68 (s, 1H), 6.56 (d, J = 7.2 Hz, 1H), 496.2(fluoromethyl)- 5.99 (d, J = 50.9 Hz, pyridin-2(1H)- 2H), 5.85-5.64 (m,one 1H), 2.89 (s, 3H), 2.08 (s, 1H), 1.73-1.54 (m, 5H), 1.49-1.25 (m,4H), 1.04 (s, 6H). 265 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 1- ¹H NMR(500 MHz, DMSO-d₆) δ 13.47 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.90 (d,J = 12.5 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.28 (d, J = 9.8 Hz, 1H),7.08 (d, J = 6.9 Hz, 1H), 6.58 (d, J = 1.7 Hz, 1H), 6.47- 6.43 (m, 1H),5.83-5.67 478.2 methylpyridin- (m, 1H), 3.46 (s, ₃ h), 2(1H)-one 2.89(s, ₃ h), 1.69-1.56 (m, 5H), 1.49-1.26 (m, 5H), 1.04 (s, ₆ h). 266 10-100

6-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- ¹H NMR (500 MHz,DMSO-d₆) δ 13.50 (s, 1H), 8.57 (s, 1H), 8.31 (d, J = 10.0 Hz, 1H), 8.00(d, J = 8.4 Hz, 1H), 7.65-7.61 (m, 2H), 7.37 (d, J = 9.9 Hz, 1H), 7.00(s, 1H), 5.95-5.85 (m, 1H) 461.0 3- 3.44 (s, 3H), 2.93 (s,methylpyrimidin- 3H), 2.19-2.12 (m, 4(3H)-one 1H), 2.01-1.88 (m, 6H),1.80-1.74 (m, 1H), 1.68-1.61 (m, 2H), 1.36 (s, 6H). 267

2-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- methoxypyridazin- 4-yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 13.89 (s, 1H), 9.35 (s, 1H), 8.34 (d, J =8.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.55- 7.46 (m, 2H)7.36 (d, J = 8.1 Hz, 1H), 5.91-5.76 (m, 1H), 4.09 (s, 3H), 2.92 (s,461.3 3H), 2.19-2.05 (m, 1H), 1.96-1.67 (m, 6H), 1.64-1.45 (m, 3H),1.37-1.09 (m, 6H). 268 <10

2-(6- ((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- (methoxy- ¹H NMR (500 MHz,DMSO-d₆) δ 13.90 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 10.0 Hz, 1H), 8.03(d, J = 8 Hz, 1H), 7.47-7.50 (m, 3H), 7.31 (d, J = 9 Hz, 1H), 5.75 (m,1H), 2.90 (s, 3H), 2.00 (m, 1H), 464.0 d3)pyridazin-4- 1.28-1.68 (m,9H), yl)phenol 1.12 (s, 6H). 269 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (6-(methoxy- ¹H NMR (500MHz, DMSO-d₆) δ 13.66 (s, 1H), 9.17 (d, J = 1.7 Hz, 1H), 8.30 (d, J =10.0 Hz, 1H), 7.99 (d, J = 12.4 Hz, 1H), 7.44 (s, 1H), 7.39-7.17 (m,2H), 5.92-5.64 (m, 1H), 2.89 (s, 3H), 482.2 d3)pyridazin-4- 2.17-1.95(m, 1H), yl)phenol 1.78-1.54 (m, 5H), 1.52-1.38 (m, 2H), 1.38-1.26 (m,2H), 1.05 (s, 6H), 270

2-(6- ((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(6- methoxypyrimidin- 4-yl)phenol¹H NMR (500 MHz, DMSO-d₆) δ 13.77 (s, 1H), 8.87 (s, 1H), 8.28 (d, J =10.0 Hz, 1H), 8.01 (d, J = 3.5 Hz, 1H), 7.76-7.74 (m, 2H), 7.54 (s, 1H),5.74 (m, 1H), 3.99 (s, 3H), 2.90 (s, 3H), 2.08 (m, 1H), 1.67-1.62 (m,461.2 5H), 1.46-1.44 (m, 2H), 1.34-1.28 (m, 2H), 1.04 (s, 6H). 271 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-4-fluoro-5- (1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.13- 8.03 (m, ₃ h), 7.61 (d, J = 12.4 Hz, 1H), 7.30 (d,J = 9.9 Hz, 1H), 7.25 (d, J = 6.7 Hz 1H), 5.84- 5.73 (m, 1H), 3.52-3.48(m, 2H), 3.02 (s, ₃ h), 2.28-2.18 (m, ₃ h), 2.10- 2.00 (m, 2H), 1.98-409.1 1.90 (m, 4H), 1.90-1.82 (m, 1H). 272 10- 100

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H- imidazol-1- yl)phenol ¹H NMR (500 MHz, DMSO-d₆)δ 14.13 (s, 1H), 9.21 (s, 1H), 8.37 (s, 1H), 8.31 (d, J = 9 Hz, 1H),8.03 (d, J = 7.5 Hz, 1H), 7.82 (s, 1H), 7.39 (d, J = 9.5 Hz, 1H), 7.30(s, 1H), 7.25 (d, J = 7 Hz, 1H), 7.11 (s, 1H), 5.70-5.75 (m, 1H), 3.73391.3 (s, 2H), 2.99 (s, ₃ h), 2.31-2.39 (m, 2H), 2.01- 2.08 (m, ₃ h),1.75-1.90 (m, 4H), 1.70-1.75 (m, 1H). 273 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2- methyloxazol- 5-yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.74 (s, 1H), 9.20 (s, 1H), 8.28 (d, J = 10 Hz, 1H), 8.00(d, J = 9 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 10 Hz, 1H), 7.25-7.23 (m,2H), 5.75 (s, 1H), 3.75 (s, 2H), 2.96 (s, ₃ h), 2.28-2.37 (m, ₃ h),1.76- 406.1 2.01 (m, ₁₀ h). 274 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-4-fluoro-5- (2- methyloxazol- 5-yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 13.32 (s, 1H), 8.30 (d, J = 9.9 Hz, 1H), 7.96 (d, J =12.5 Hz, 1H), 7.44 (d, J = 3.5 1H), 7.37 (d, J = 9.9 Hz, 1H), 7.22 (d, J= 6.5 Hz, 1H), 5.84-5.70 (m, 1H), 3.76-3.68 (m, 2H), 2.97 (s, ₃ h), 2.52(s, ₃ h), 424.2 2.38-2.27 (m, 2H), 2.09- 1.75 (m, ₈ h). 275 <10 <10 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2H-1,2,3- triazol-2- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 13.81 (s, 1H), 8.28 (d, J = 10.0 Hz, 1H), 8.15 (s, 2H), 8.10(d, J = 8.7 Hz, 1H), 7.66-7.50 (m, 2H), 7.40 (d, J = 9.9 Hz, 1H), 5.89-5.59 (m, 1H), 3.76 (s, 2H), 2.96 (s, ₃ h), 2.38- 2.32 (m, 2H), 2.11-1.83392.3 (m, ₈ h). 276 101- 250

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)oxy)pyridazin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.21 (s,1H), 13.02 (s, 1H), 8.44 (d, J = 9.6 Hz, 1H), 8.18 (s, 2H), 7.93 (d, J =8.3 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 7.30-7.25 (m, 2H), 6.05 (s, 1H),3.20 (s, 2H), 2.32-2.25 (m, 378.2 2H), 1.94-1.82 (m, 4H), 1.76-1.70 (m,4H). 277 >1000 >1000 >1000

2-(6- (((1R,3r,5S)-9- azabicyclo[3.3.1] nonan-3- yl)oxy)pyridazin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ 13.29 (s,1H), 13.21-12.89 (m, 1H), 8.45 (d, J = 9.6 Hz, 1H), 8.15 (s, 2H), 7.93(d, J = 8.3 Hz, 1H), 7.40 (d, J = 9.5 Hz, 1H), 7.28- 7.18 (m, 2H),5.40-5.35 (m, 1H), 3.29 (d, J = 9.4 378.3 Hz, 2H), 2.48-2.42 (m, 2H),2.15-2.08 (m, 1H), 1.69-1.58 (m, 4H), 1.48- 1.45 (m, ₃ h). 278 10- 100

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)oxy)pyridazin-3-yl)-4- fluoro-5-(1H- pyrazol-4- yl)phenol ¹H NMR (500 MHz, DMSO-d₆) δ8.43 (d, J = 9.5 Hz, 1H), 8.13 (s, 2H), 7.89 (d, J = 12.2 Hz, 1H),7.42-7.31 (m, 2H), 6.12-6.00 (m, 1H), 3.24-3.18 (m, 2H), 2.28- 2.20 (m,2H), 2.07 (s, ₃ h), 1.85-1.60 (m, ₈ h). 396.1 279 10- 100 <10 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1H-1,2,3- triazol-1- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 14.08 (s, 1H), 8.92 (s, 1H), 8.79- 8.41 (m, 1H), 8.31 (d, J =10.0 Hz, 1H), 8.13 (d, J = 8.6 Hz 1H) 8.00 (s, 1H), 7.57-7.48 (m, 2H),7.41 (d, J = 9.9 Hz, 1H), 5.88-5.58 (m, 1H), 3.68 392.3 (s, 2H), 2.96(s, ₃ h), 2.37-2.31 (m, 2H), 2.07- 1.65 (m, ₈ h). 280 10- 100

5-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 2- methylpyridazin- 3(2H)-one ¹H NMR(500 MHz, DMSO-d₆) δ 13.87 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.33 (d, J= 10.0 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.45-7.35 (m, ₃ h), 7.27 (d, J= 2.2 Hz, 1H), 5.73 (m, 1H), 3.69 (s, ₃ h), 3.59 (s, 2H), 2.96 (s, ₃ h),2.22 (m, 2H), 2.09-1.79 (m, ₈ h), 1.79- 433.1 1.69 (m, 1H). 281 <10 <10<10

5-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 2-(methyl- d3)pyridazin- 3(2H)-one¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 9.9Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.44-7.38 (m, 2H), 7.35 (d, J = 9.9Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 5.75-5.63 (m, 1H), 2.95 (s, ₃ h),2.13- 1.95 (m, ₃ h), 1.92-1.81 (m, 2H), 1.73 (m, 5H). 436.1 282 10- 100<10 10- 100

5-(4-(6- (((1R,3s,5S)-8- azabicyclo[3.2.1] octan-3- yl)(methyl)amino)pyridazin-3- hydroxyphenyl)- 2-(methyl- d3)pyridazin- 3(2H)-one ¹H NMR(500 MHz, DMSO-d₆) δ 8.39 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 10.0 Hz,1H), 8.02 (d, J = 8.2 Hz, 1H), 7.44- 7.36 (m, ₃ h), 7.27 (d, J = 2.2 Hz,1H), 5.02-4.86 (m, 1H), 3.55 (s, 2H), 2.95 (s, ₃ h), 1.88-1.72 (m, ₆ h),1.59-1.46 (m, 2H). 422.2 283 <10

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1- methylpyridin- ¹H NMR (500 MHz,DMSO-d₆) δ 8.22 (d, J = 9.9 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.78 (d,J = 7.1 Hz, 1H), 7.34-7.25 (m, ₃ h), 6.74 (d, J = 2.0 Hz, 1H), 6.67 (dd,J = 7.1, 2.1 Hz, 1H), 5.74- 5.60 (m, 1H), 3.48 (s, ₃ h) 3.25-3.15 (m,2H), 432.1 2(1H)-one 2.94 (s, ₃ h), 2.09-1.92 (m, ₃ h), 1.90-1.79 (m,2H), 1.74-1.61 (m, 5H). 284 <10 >1000 <10

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1-(methyl- d3)pyridin- 2(1H)-one ¹HNMR (500 MHz, DMSO-d₆) δ 13.75 (s, 1H), 8.28 (d, J = 9.9 Hz, H), 7.98(d, J = 8.3 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 10.0 Hz,1H), 7.30-7.24 (m, 2H), 6.70 (d, J = 2.1 Hz, 1H), 6.61 (dd, J = 7.2, 2.1Hz, 1H), 5.75-5.64 (m, 1H), 3.45 (s, 2H), 2.95 (s, ₃ h), 2.15-1.72 435.3(m, ₁₀ h). 285 <10 >1000 <10

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 1- methylpyridin- ¹H NMR(500 MHz, DMSO-d₆) δ 13.47 (s, 1H), 8.27 (d, J = 9.9 Hz, 1H), 7.91 (d, J= 12.4 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.08(d, J = 6.9 Hz, 1H), 6.58 (s, 1H), 6.45 (d, J = 7.1 Hz, 1H), 5.73-5.61(m, 1H), 3.46 450.2 2(1H)-one (s, ₃ h), 3.24-3.15 (m, 2H), 2.94 (s, ₃h), 2.06- 1.93 (m, ₃ h), 1.86-1.76 (m, 2H), 1.74-1.60 (m, 5H). 286 <10

5-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)- 2- methylpyridazin- ¹H NMR(500 MHz, DMSO-d₆) δ 8.29 (d, J = 9.9 Hz, 1H), 8.19 (t, J = 2.0 Hz, 1H),7.97 (d, J = 12.3 Hz, 1H), 7.33 (d, J = 9.9 Hz, 1H), 7.24 (d, J = 6.9Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 5.76- 5.62 (m, 1H), 3.70 (s, ₃ h),3.21-3.15 (m, 2H), 451.2 3(2H)-one 2.94 (s, ₃ h), 2.06-1.92 (m, ₃ h),1.84-1.75 (m, 2H), 1.74-1.62 (m, 5H). 287 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1-methyl- 1H-pyrazol-4- yl)phenol ¹H NMR (500 MHz,DMSO-d₆) δ 8.18 (d, J = 9.4 Hz, 2H), 7.91 (s, 1H), 7.82 (d, J = 8.8 Hz,1H), 7.30 (d, J = 9.9 Hz, 1H), 7.15 (s, 2H), 5.70- 5.54 (m, 1H), 3.87(s, ₃ h), 3.31-3.19 (m, 2H), 2.93 (s, ₃ h), 2.08-1.66 (m, ₁₀ h). 405.2288 10- 100

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1- (methyl-d3)- 1H-pyrazol-4- yl)phenol ¹H NMR (500MHz, DMSO-d₆) δ 8.17 (d, J = 9.6 Hz, 2H), 7.91 (s, 1H), 7.82 (d, J = 8.8Hz, 1H), 7.30 (d, J = 9.9 Hz, 1H), 7.16 (d, J = 5.5 Hz, 2H), 5.63-5.60(m, 1H), 3.24 (s, 2H), 2.92 (s, ₃ h), 2.05-1.94 (m, ₃ h), 1.85 (s, 2H),1.73-1.63 (m, 408.1 5H). 289 <10

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(2- methoxypyridin- 4-yl)phenol ¹H NMR (500 MHz,Methanol-d₄) δ 8.33 (d, J = 9.8 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.89(d, J = 8.4 Hz, 1H), 7.64- 7.59 (m, 1H), 7.41-7.35 (m, 2H), 7.34-7.31(m, 1H), 7.15 (d, J = 1.5 Hz, 1H), 5.86 (s, 1H), 4.02 (s, ₃ h), 3.89 (s,2H), 3.08 432.1 (s, ₃ h), 2.44-2.35 (m, 2H), 2.24-2.33 (m, 1H),2.21-2.07 (m, ₆ h), 1.96- 1.89 (m, 1H). 290 251- 500

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1,6- dimethylpyridin- 2(1H)-one ¹HNMR (500 MHz, DMSO-d₆) δ 8.25 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 8.2 Hz,1H), 7.33 (d, J = 9.9 Hz, 1H), 7.30- 7.22 (m, 2H), 6.64-6.57 (m, 2H),5.75-5.62 (m, 1H), 3.35 (d, J = 5.3 Hz, 2H), 3.32 (s, ₃ h), 2.94 (s, ₃h), 2.44 (s, ₃ h), 2.12- 1.68 (m, ₁₀ h). 446.3 291 <10

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 1- (fluoromethyl) ¹H NMR (500 MHz,DMSO-d₆) δ 13.79 (s, 1H), 8.30 (d, J = 9.9 Hz, 1H), 8.01 (d, J = 8.2 Hz,1H), 7.90 (d, J = 7.3 Hz, 1H), 7.41-7.25 (m, ₃ h), 6.81 (d, J = 1.6 Hz,1H), 6.77-6.68 (m, 1H), 5.99 (d, J = 51 Hz, 2H), 5.72- 5.69 (m, 1H),3.50 (s, 450.3 pyridin-2(1H)- 2H), 2.96 (s, ₃ h), 2.26- one 2.12 (m,2H), 2.07-1.63 (m, ₈ h). 292 >1000

4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3′-methoxy- 4′-methyl-[1,1′- biphenyl]-3-ol ¹H NMR (500MHz, DMSO-d₆) δ 8.18 (d, J = 9.7 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H),7.34-7.15 (m, ₆ h) 5.64-5.56 (m, 1H), 3.89 (s, ₃ h), 3.23 (s, 2H), 2.94(s, ₃ h), 2.20 (s, ₃ h), 2.06-1.75 (m, ₃ h), 1.58-1.45 (m, ₃ h), 1.65-1.49 (m, 5H). 445.1 293 10- 100

4-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl) pyridin-2(1H)- one ¹H NMR (500 MHz,DMSO-d₆) δ 8.25 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.45 (d,J = 6.8 Hz, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.28- 7.20 (m, 2H), 6.62 (d,J = 1.3 Hz, 1H), 6.55 (dd, J = 6.9, 1.7 Hz, 1H), 5.65-5.59 (m, 1H), 3.17418.1 (s, 2H), 2.94 (s, ₃ h), 2.01-1.91 (m, ₃ h), 1.83- 1.65 (m, ₆ h).294 501- 1000

6-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-hydroxy- N- ¹H NMR (500 MHz, DMSO-d₆) δ 13.29 (s,1H), 8.62 (q, J = 4.6 Hz, 1H), 8.30 (d, J = 10.0 Hz, 1H), 8.12 (s, 1H),7.36 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.20 (s, 1H), 5.71-5.59 (m, 1H),422.1 methylbenzo- 3.27 (s, 2H), 2.94 (s, ₃ h), furan-2- 2.81 (d, J =4.7 Hz, ₃ h), carboxamide 2.08-1.96 (m, ₃ h), 1.90- 1.78 (m, 2H), 1.73-1.67 (m, 5H). 295 251- 500

6-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-hydroxy- N,N- dimethylbenzo- ¹H NMR (500 MHz,Methanol-d₄) δ 8.20 (d, J = 9.9 Hz, 1H), 8.04 (s, 1H), 7.34-7.28 (m,2H), 7.21 (s, 1H), 5.83-5.70 (m, 1H), 3.45-3.37 (m, 5H), 3.17 (s, ₃ h),3.03 (s, ₃ h), 2.27-2.14 (m, ₃ h), 2.09-1.96 (m, 2H), 1.96- 436.3furan-2- 1.80 (m, 5H). carboxamide 296 101- 250 <10 10- 100

6-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-N- cyclopropyl-5- ¹H NMR (500 MHz, DMSO-d₆) δ 13.31 (s,1H), 8.68 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 9.8 Hz, 1H), 8.11 (s, 1H),7.40 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.20 (s, 1H), 5.80-5.51 (m, 1H),3.23 448.2 hydroxybenzo- (s, 2H), 2.94 (s, ₃ h), 2.91- furan-2- 2.80 (m,1H), 2.05- carboxamide 1.93 (m, ₃ h), 1.87-1.78 (m, 2H), 1.73-1.63 (m,5H), 0.75-0.59 (m, 4H). 297 10- 100

5-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-6-hydroxy- N- ¹H NMR (500 MHz, DMSO-d₆) δ 8.60-8.56 (m,1H), 8.28 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J =9.9 Hz, 1H), 7.12 (s, 1H), 5.68-5.65 (m, 1H), 3.27-3.23 (m, 2H), 422.1methylbenzo- 2.93 (s, ₃ h), 2.79 (d, J = furan-2- 4.6 Hz, ₃ h),2.09-1.92 carboxamide (m, ₃ h), 1.85-1.81 (m, 2H), 1.71-1.67 (m, 5H).298 10- 100

5-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-6-hydroxy- N,N- dimethylbenzo- ¹H NMR (500 MHz,DMSO-d₆) δ 8.25-8.23 (m, 2H), 7.36-7.34 (m, 2H), 7.16 (s, 1H), 5.66-5.64 (m, 1H), 3.29- 3.25(m, 2H), 3.20 (s, ₃ h), 3.03 (s, ₃ h), 2.93 (s,₃ h), 2.00-1.96 (m, ₃ h), 1.82- 1.78 (m, 2H), 1.71-1.67 436.0 furan-2-(m, 5H). carboxamide 299 10- 100

5-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-N- cyclopropyl-6- ¹H NMR (500 MHz, DMSO-d₆) δ 8.25-8.234.0 Hz, 1H), 8.30 (d, J = 10.0 Hz, 1H),8.29 (s, 1H), 7.45 (s, 1H), 7.40(d, J = 10.0 Hz, 1H), 7.11 (s, 1H), 5.75-5.72 (m, 1H), 3.69-3.65 (m,448.3 hydroxybenzo- 2H), 2.95 (s, ₃ h), 2.86- furan-2- 2.84 (m, 1H),2.22 (s, carboxamide 2H), 2.13-1.65 (m, ₈ h), 0.82-0.52 (m, 4H). 300 10-100

6-(4-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-3- hydroxyphenyl)- 3- methylpyrimidin- ¹H NMR (500 MHz,DMSO-d₆) δ 13.71 (s, 1H), 8.56 (s, 1H), 8.26 (d, J = 9.9 Hz, 1H), 7.97(d, J = 8.2 Hz, 1H), 7.64- 7.58 (m, 2H), 7.31 (d, J = 9.9 Hz, 1H), 7.00(s, 1H), 5.72-5.61 (m, 1H), 3.44 (s, ₃ h), 3.21-3.16 (m, 2H), 2.94 (s, ₃h), 433.3 4(3H)-one 2.03-1.93 (m, ₃ h), 1.86- 1.76 (m, 2H), 1.74- 1.62(m, 5H). 301 10- 100

2-(6- (((1R,3s,5S)-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino)pyridazin-3- yl)-5-(1- (difluoromethyl)- 1H-pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO-d₆) δ 13.86 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 8.27 (d,J = 10.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.85 (t, J = 59.5 Hz, 1H),7.38-7.23 (m, ₃ h), 5.82-5.64 (m, 1H), 3.54 (s, 2H), 2.95 (s, ₃ h),2.25-2.15 (m, 2H), 2.03- 441.3 1.70 (m, ₈ h). 302 10- 100

2-(6- (cyclopropyl ((1R,3s,5S)-1,5- dimethyl-8- azabicyclo[3.2.1]octan-3- yl)amino)pyrid- azin-3-yl)-5-(1H- pyrazol-4- yl)phenol ¹H NMR(500 MHz, DMSO-d₆) δ 8.25 (d, J = 9.8 Hz, 1H), 8.12 (s, 2H), 7.84 (d, J= 8.3 Hz, 1H), 7.54 (d, J = 9.7 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 4.81-4.65 (m, 1H), 1.87-1.63 (m, 7H), 1.47 (d, J = 7.2 Hz, 2H),1.17 (s, 431.2 6H), 0.98 (d, J = 5.5 Hz, 2H), 0.65 (s, 2H). 303 10- 100

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-5-(2- (methyl- d3)oxazol-5- ¹H NMR(500 MHz, DMSO-d₆) δ 13.89 (s, 1H), 8.22 (d, J = 10.0 Hz, 1H), 7.95 (d,J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.37 (d, J = 9.9 Hz, 1H), 7.25-7.18 (m,2H), 5.02- 4.90 (m, 1H), 2.94 (s, ₃ h), 1.89-1.80 (m, 2H), 1.65-1.52 (m,₆ h), 1.18 423.3 yl)phenol (s, ₆ h). 304 10- 100 >1000 <10

2-(6- (((1R,3s,5S)- 1,5-dimethyl-8- azabicyclo[3.2.1] octan-3-yl)(methyl)amino) pyridazin-3- yl)-4-fluoro-5- (2-(methyl- d3)oxazol-5-¹H NMR (500 MHz, DMSO-d₆) δ 13.52 (s, 1H), 8.24 (d, J = 9.9 Hz, 1H),7.94 (d, J = 12.4 Hz, 1H), 7.44 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 9.8Hz, 1H), 7.21 (d, J = 6.5 Hz, 1H), 4.99-4.90 (m, 1H), 2.94 (s, ₃ h),1.84- 1.78 (m, 2H), 1.55-1.47 441.3 yl)phenol (m, ₆ h), 1.17 (s, ₆ h).305 101- 250

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl)- ¹H NMR (500 MHz,DMSO-d₆) δ 13.69 (s, 1H), 8.34-8.20 (m, 2H), 8.01 (d, J = 8.5 Hz, 1H),7.74-7.60 (m, 2H), 7.29 (d, J = 10.1 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H),5.84-5.65 (m, 1H), 3.47 (s, ₃ h), 2.89 (s, ₃ h), 1.72- 461.3 1- 1.55 (m,4H), 1.52- methylpyrimidin- 1.20 (m, ₆ h), 1.04 (s, ₆ h). 2(1H)-one 306<10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-3- hydroxyphenyl) pyridin-2(1H)- ¹HNMR (500 MHz, DMSO-d₆) δ 13.59 (s, 1H), 11.61 (s, 1H), 8.30 (d, J = 10.0Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J = 9.9 Hz,1H), 7.26 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 6.61 (s, 1H),6.52 (s, 1H), 5.89- 446.0 one 5.85 (m, 1H), 2.92 (s, ₃ h), 2.16-2.12 (m,1H), 2.05-1.84 (m, ₆ h), 1.74- 1.70 (m, ₃ h), 1.36 (s, ₆ h). 307 10- 100<10 <10

4-(4-(6- (((1R,3s,5S)- 1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3-yl)(methyl)amino) pyridazin-3- yl)-2-fluoro-5- hydroxyphenyl)pyridin-2(1H)- ¹H NMR (500 MHz, DMSO-d₆) δ 13.25 (s, 1H), 11.71 (s, 1H),9.17 (s, 1H), 8.65 (s, 1H), 8.31 (d, J = 10.0 Hz, 1H), 7.93 (d, J = 12.3Hz, 1H), 7.47 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.07 (d, J= 6.9 Hz, 1H), 6.50 (s, 1H), 464.0 one 6.38 (d, J = 7.2 Hz, 1H), 5.89(m, 1H), 2.96 (s, ₃ h), 2.14 (m, 1H), 2.06- 1.84 (m, ₆ h), 1.80-1.60 (m,₃ h), 1.38 (s, ₆ h). 308 501- 1000

5-(2- (difluoromethoxy) pyridin-4-yl)- 2-(6- (((1R,3s,5S)-1,5-dimethyl-9- azabicyclo[3.3.1] nonan-3- yl)(methyl)amino) ¹H NMR (500MHz, DMSO-d₆) δ 13.76 (s, 1H), 9.25-9.12 (m, 1H), 8.70-8.59 (m, 1H),8.38- 8.30 (m, 2H), 8.07- 8.01 (m, 1H), 7.77 (t, J = 73 Hz, 1H),7.68-7.65 (m, 1H), 7.48-7.34 (m, 4H), 5.96-5.83 (m, 1H), 496.3pyridazin-3- 2.97 (s, ₃ h), 2.05-1.86 yl)phenol (m, 5H), 1.79-1.61 (m, ₃h), 1.39 (s, ₆ h). ^(A)Cell viability ^(B)FoxM1 A mRNA increase (exonexcluded) ^(C)FoxM1 BC mRNA decrease (exon included)

TABLE 1C Exemplary SMSM compounds SMSM# Structure Name 309

3-amino-1-(4-(cyclopropyl(6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 310

3-amino-1-(4-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 311

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)thio)-2,2,6,6-tetramethylpiperidin- 1-yl)propan-1-one 312

3-amino-1-((1R,3s,5S)-3-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8- azabicyclo[3.2.1]octan-8-yl)propan-1-one 313

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 314

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-2,2,6,6-tetramethylpiperidin- 1-yl)propan-1-one 315

3-amino-1-((1R,5S)-6-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)propan- 1-one 316

3-amino-1-(4-(cyclobutyl(6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 317

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)(methoxy)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 318

3-amino-1-(1-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)octahydro-5H-pyrrolo[3,2- c]pyridin-5-yl)propan-1-one 319

3-amino-1-(1-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)octahydro-1,6-naphthyridin- 6(2H)-yl)propan-1-one 320

3-amino-1-(1-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)-1,7-diazaspiro[3.5]nonan-7- yl)propan-1-one 321

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)thio)piperidin-1-yl)propan-1-one 322

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-2,2,6,6-tetramethylpiperidin- 1-yl)propan-1-one 323

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 324

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)(2-methoxyethoxy)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 325

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)methylene)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 326

3-amino-1-(4-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)piperidin-1-yl)propan-1- one 327

3-amino-1-(4-(hydroxy(6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)methyl)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 328

3-amino-1-(4-((6-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methoxy)methyl)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one329

3-amino-1-(4-(6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazine-3-carbonyl)-2,2,6,6- tetramethylpiperazin-1-yl)propan-1- one 330

3-amino-1-(4-((6-(2-hydroxy-4-(1H- pyrazol-4-yl)phenyl)pyridazin-3-yl)(trifluoromethyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1-one 331

3-amino-1-(4-((2-fluoroethyl)(6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 332

3-amino-1-(4-((6-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2,2,2-trifluoroethyl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 333

3-amino-1-(4-((3-fluoropropyl)(6- (2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 334

3-amino-1-(4-((6-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(2-methoxyethyl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)propan-1-one 335

3-amino-1-((1R,3s,5S)-3-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8- azabicyclo[3.2.1]octan-8-yl)propan-1-one 336

3-amino-1-((1R,3r,5S)-3-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8- azabicyclo[3.2.1]octan-8-yl)propan-1-one 337

3-amino-1-((1R,3s,5S)-3-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propan- 1-one 338

3-amino-1-((1R,3r,5S)-3-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propan- 1-one 339

3-amino-1-(3-((6-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-8-azabicyclo[3.2.1]octan- 8-yl)propan-1-one 340

3-amino-1-(4-((5-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(methyl)amino)piperidin-1- yl)propan-1-one 341

3-amino-1-(4-((5-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan- 1-one 342

3-amino-1-(4-((5-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyrazin-2-yl)oxy)-2,2,6,6- tetramethylpiperidin-1-yl)propan- 1-one 343

3-amino-1-(4-((6-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyridin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 344

3-amino-1-(4-((2-(2-hydroxy-4- (1H-pyrazol-4-yl)phenyl)pyrimidin-5-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)propan-1- one 345

5-(4-(5-((1-(3-aminopropanoyl)- 2,2,6,6-tetramethylpiperidin-4-yl)(methyl)amino)pyrazin-2-yl)-3- hydroxyphenyl)pyrimidin-2(1H)- one 346

1-(4-((4-(5-(1H-pyrazol-4- yl)pyrimidin-2-yl)-3-hydroxyphenyl)(methyl)amino)- 2,2,6,6-tetramethylpiperidin-1-yl)-3-aminopropan-1-one 347

2′-(4-((1-(3- aminopropanoyl)piperidin-4- yl)(methyl)amino)-2-hydroxyphenyl)-[5,5′-bipyrimidin]- 2(1H)-one 348

(E)-3-(4-aminophenyl)-1-(4-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)prop-2- en-1-one 349

3-(4-aminophenyl)-1-(4-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)propan- 1-one 350

1-(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)-2-(piperidin-4-yl)ethan-1-one 351

4-(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidine-1-carbonyl)cyclohexane-1-carboxylic acid 352

1-(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)-2-(2-(methylamino)ethoxy)ethan-1-one 353

4-((6-(2-hydroxy-4-(1H-pyrazol-4- yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethyl-N-(3-(methylamino)propyl)piperidine-1- carboxamide 354

(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)(piperidin-4-yl)methanone 355

1-(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)-2- (methyl(2-(methylamino)ethyl)amino)ethan-1- one 356

2-(azetidin-3-yl)-1-(4-((6-(2- hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3- yl)(methyl)amino)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1- one 357

1-(4-((6-(2-hydroxy-4-(1H-pyrazol- 4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-2,2,6,6- tetramethylpiperidin-1-yl)pent-4- yn-1-one

In some embodiments, a compound is selected from:

-   6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-chloro-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(4-chloro-2-methoxyphenyl)-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   N-cyclopropyl-6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   tert-butyl    (1R,3S,5S)-3-((6-chloropyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl    (1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-methoxyphenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl(1R,3s,5S)-3-((6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl(1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl    (1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate;-   tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate;-   (1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   (1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   (1R,3s,5S)-9-(4-methoxybenzyl)-N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate;-   (1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   (1R,3s,5S)—N-(6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)    pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   (1R,3s,5S)—N-(6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine;-   tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate;-   tert-butyl    (1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate;-   2tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate;-   (1R,3s,5S)-3-(6-chloropyridazin-3-yloxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane;    and-   (1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane.

In some embodiments, an SMSM described herein, possesses one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In certainembodiments, compounds described herein are prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds/salts, separating the diastereomers and recovering theoptically pure enantiomers. In some embodiments, resolution ofenantiomers is carried out using covalent diastereomeric derivatives ofthe compounds described herein. In another embodiment, diastereomers areseparated by separation/resolution techniques based upon differences insolubility. In other embodiments, separation of stereoisomers isperformed by chromatography or by the forming diastereomeric salts andseparation by recrystallization, or chromatography, or any combinationthereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In oneaspect, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In one aspect, prodrugs are designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacokinetic, pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is known, the design of prodrugsof the compound is possible. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho,“Recent Advances in Oral Prodrug Discovery”, Annual Reports in MedicinalChemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

In some cases, some of the herein-described compounds may be a prodrugfor another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactionsTherefore incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ₃h, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³ ₆ cl. Inone aspect, isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. In one aspect, substitution with isotopes such as deuteriumaffords certain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms, particularlysolvates. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and may be formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. In some embodiments,solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein can exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

In some embodiments, an SMSM has a molecular weight of at most about2000 Daltons, 1500 Daltons, 1000 Daltons or 900 Daltons. In someembodiments, an SMSM has a molecular weight of at least 100 Daltons, 200Daltons, 300 Daltons, 400 Daltons or 500 Daltons. In some embodiments,an SMSM does not comprise a phosphodiester linkage.

Methods of Making Compounds

Compounds described herein can be synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein. Unless otherwise indicated, conventional methods ofmass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,recombinant DNA techniques and pharmacology can be employed. Compoundscan be prepared using standard organic chemistry techniques such asthose described in, for example, March's Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions forthe synthetic transformations described herein may be employed such asvariation of solvent, reaction temperature, reaction time, as well asdifferent chemical reagents and other reaction conditions. The startingmaterials can be available from commercial sources or can be readilyprepared. By way of example only, provided are schemes for preparing theSMSMs described herein.

In some embodiments, a scheme for preparing an SMSM described herein isScheme 1:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 2:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 3:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 4:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 5:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 6:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 7:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 8:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 9:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 10:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 11:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 12:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 13:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 14

In some embodiments, a scheme for preparing an SMSM described herein isScheme 15:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 16

In some embodiments, a scheme for preparing an SMSM described herein isScheme 17:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 18:

In some embodiments, a scheme for preparing an SMSM described herein isScheme 19:

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

SMSMs can be made using known techniques and further chemicallymodified, in some embodiments, to facilitate intranuclear transfer to,e.g., a splicing complex component, a spliceosome or a pre-mRNAmolecule. One of ordinary skill in the art will appreciate the standardmedicinal chemistry approaches for chemical modifications forintranuclear transfer (e.g., reducing charge, optimizing size, and/ormodifying lipophilicity).

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

A pharmaceutical composition can be a mixture of an SMSM describedherein with one or more other chemical components (i.e. pharmaceuticallyacceptable ingredients), such as carriers, excipients, binders, fillingagents, suspending agents, flavoring agents, sweetening agents,disintegrating agents, dispersing agents, surfactants, lubricants,colorants, diluents, solubilizers, moistening agents, plasticizers,stabilizers, penetration enhancers, wetting agents, anti-foaming agents,antioxidants, preservatives, or one or more combination thereof. Thepharmaceutical composition facilitates administration of the compound toan organism.

The compositions described herein can be administered to the subject ina variety of ways, including parenterally, intravenously, intradermally,intramuscularly, colonically, rectally or intraperitoneally. In someembodiments, the small molecule splicing modulator or a pharmaceuticallyacceptable salt thereof is administered by intraperitoneal injection,intramuscular injection, subcutaneous injection, or intravenousinjection of the subject. In some embodiments, the pharmaceuticalcompositions can be administered parenterally, intravenously,intramuscularly or orally. The oral agents comprising a small moleculesplicing modulator can be in any suitable form for oral administration,such as liquid, tablets, capsules, or the like. The oral formulationscan be further coated or treated to prevent or reduce dissolution instomach. The compositions of the present invention can be administeredto a subject using any suitable methods known in the art. Suitableformulations for use in the present invention and methods of deliveryare generally well known in the art. For example, the small moleculesplicing modulators described herein can be formulated as pharmaceuticalcompositions with a pharmaceutically acceptable diluent, carrier orexcipient. The compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionsincluding pH adjusting and buffering agents, tonicity adjusting agents,wetting agents and the like, such as, for example, sodium acetate,sodium lactate, sodium chloride, potassium chloride, calcium chloride,sorbitan monolaurate, triethanolamine oleate, etc.

Pharmaceutical formulations described herein can be administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the pharmaceutical formulation is in the form of atablet. In other embodiments, pharmaceutical formulations containing anSMSM described herein are in the form of a capsule. In one aspect,liquid formulation dosage forms for oral administration are in the formof aqueous suspensions or solutions selected from the group including,but not limited to, aqueous oral dispersions, emulsions, solutions,elixirs, gels, and syrups.

For administration by inhalation, an SMSM described herein can beformulated for use as an aerosol, a mist or a powder. For buccal orsublingual administration, the compositions may take the form oftablets, lozenges, or gels formulated in a conventional manner. In someembodiments, an SMSM described herein can be prepared as transdermaldosage forms. In some embodiments, an SMSM described herein can beformulated into a pharmaceutical composition suitable for intramuscular,subcutaneous, or intravenous injection. In some embodiments, an SMSMdescribed herein can be administered topically and can be formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams or ointments. In some embodiments, an SMSM described herein canbe formulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas.

Splicing

Extensive posttranscriptional processing occurs before eukaryoticpre-mRNA matures and exits from the nucleus to the cytoplasm, includingthe addition of a 7-methylguanosine cap at the 5′ end, the cleavage andaddition of a poly-A tail at the 3′ end as well as the removal ofintervening sequences or introns by the spliceosome. The vast majorityof higher eukaryotic genes contain multiple introns that are spliced outwith high precision and fidelity in order to maintain the reading frameof the exons. Splicing of pre-mRNA can utilize the recognition of shortconsensus sequences at the boundaries and within introns and exons by anarray of small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNPsU1, U2, U4, U5, U6, U11, U12m U4atc and U6 atc) and a large number ofproteins, including spliceosomal proteins and positively as well asnegatively acting splicing modulators.

Serine-arginine-rich (SR)-domain-containing proteins generally serve topromote constitutive splicing.

They can also modulate alternative splicing by binding to intronic orexonic splicing enhancer (ISE) or ESE, respectively) sequences. Otherpre-mRNA binding proteins, such as hnRNPs, regulate splicing by bindingto intronic or exonic splicing suppressor (ISS or ESS, respectively)sequences and can also act as general splicing modulators. The SRprotein family is a class of at least 10 proteins that have acharacteristic serine/arginine rich domain in addition to anRNA-binding. SR proteins are generally thought to enhance splicing bysimultaneously binding to U170K, a core component of the U1 snRNP, atthe 5′ splice site, and the U2AF35 at the 3′ splice site, thus bridgingthe two ends of the intron. While this particular function of SRproteins seems to be redundant, as any individual SR protein can commita pre-mRNA for constitutive splicing, the role of the various SRproteins in alternative splicing of specific pre-mRNAs is distinct duein part to their ability to recognize and bind to unique consensussequences. Phosphorylation of the RS domain of SR proteins can lead tothe regulation of their protein interactions, RNA binding, localization,trafficking, and role in alternative splicing. Several cellular kinasesthat phosphorylate SR proteins have been identified, including SRprotein Kinase (SRPKs), Cdc2-like kinases (Clks), pre-mRNA processingmutant 4 (PRP4), and topoisomerase I. Optimal phosphorylation of SRproteins may be required for proper functioning as both hypo- andhyperphosphorylation of the RS domains may be detrimental to their rolein constitutive and alternative splicing.

In higher eukaryotes, the vast majority of genes contain one or moreintrons, which creates a situation in which the exons are splicedtogether to generate mature mRNA and microRNA (miRNA). In the hostnucleus, pre-mRNA splicing is the mechanism by which introns are removedfrom a pre-mRNA and the exons are ligated together to generate maturemRNAs and pre-miRNA that is then exported to the cytoplasm fortranslation into the polypeptide gene product. Splicing of pre-mRNA canoccur in cis, where two exons derive from two adjacent cotranscribedsequences, or in trans, when the two exons come from different pre-mRNAtranscripts. The ratio of the different protein products (isoforms) maybe due to the frequency of alternative splicing events within a pre-mRNAthat leads to different amounts of distinct splice variants. In someembodiments, alternative splicing of a pre-mRNA may lead to 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 proteinisoforms being expressed.

Aberrations in splicing are thought to be the cause of roughly half ofall inherited diseases. Aberrant splicing due to mutations in consensussequences involved in exon-intron boundary recognition is responsiblefor up to 15% of inherited diseases. In addition, defects in thesplicing machinery itself due to the loss or gain of function ofsplicing factors and modulators are causes of a wide range of humanailments from cancer to neurodegenerative diseases. Both constitutiveand alternative splicing are subject to regulation by upstream signalingpathways. This regulation can be essential during development, in tissuespecific expression of certain isoforms, during the cell cycle and inresponse to extrinsic signaling molecules.

Alternative splicing allows for a single gene to express differentisoforms of mRNA, thus playing a major role in contributing to thecellular complexity in higher eukaryotes without the need to expand thegenome. Splicing can also be subject to regulation by upstream signalingpathways. For example, an upstream signaling pathway may modulatealternative splicing and increase or decrease expression levels ofdifferent isoforms of mRNA.

Alternative splicing events are highly regulated by numerous splicingfactors in a tissue type-, developmental stage-, and signal-dependentmanner. Furthermore, non-mutation based causes of splicing defects anddefects in the splicing machinery itself, e.g., due to the loss/gain offunction of splicing factors or their relative stoichiometry, cause of awide range of human ailments, ranging from cancer to neurodegenerativediseases. In many diseases the disease state is caused by an alterationof the ratio of different isoforms of two or more proteins expressedfrom a gene. In some embodiments, the alteration in the ratio of theprotein products is due to changes in the frequency of alternativesplicing events within a pre-mRNA, leading to changes in the ratio ofsplice variants produced. In some embodiments, alternative splicing of apre-mRNA may lead to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19 or 20 protein isoforms being expressed. In some embodiments,a change in the splice variant ratio is caused by genetic mutation.

In eukaryotes, the vast majority of splicing processes are catalyzed bythe spliceosome, an RNA-protein complex that occurs in unique steps andmay comprise a subset of several hundred different proteins, in additionto five spliceosomal snRNAs. These factors are responsible for theaccurate positioning of the spliceosome on the 5′ and 3′ splice sitesequences. The reason why so many factors are needed reflects theobservation that exon recognition can be affected by many pre-mRNAfeatures such as exon length, sequence recognition, the presence ofenhancer and silencer elements, the strength of upstream splicingsignals, the promoter architecture, and the rate of RNA processivity,secondary and tertiary RNA structure.

All mammalian diseases are ultimately mediated by the transcriptome.Insofar as messenger mRNA (mRNA) is part of the transcriptome, and allprotein expression derives from mRNAs, there is the potential tointervene in protein-mediated diseases by modulating the expression ofthe relevant protein and by, in turn, modulating the translation of thecorresponding upstream mRNA. But mRNA is only a small portion of thetranscriptome: other transcribed RNAs also regulate cellular biologyeither directly by the structure and function of RNA structures (e.g.,ribonucleoproteins) as well as via protein expression and action,including (but not limited to) microRNA (miRNA), long noncoding RNA(lncRNA), long intergenic noncoding RNA (lincRNA), small nucleolar RNA(snoRNA), small nuclear RNA (snRNA), small Cajal body-specific RNA(scaRNA), piwi-interacting RNA (piRNA), competing endogenous (ceRNA),and pseudo-genes. Drugs that intervene at this level have the potentialof modulating any and all cellular processes. Existing therapeuticmodalities such as antisense RNA or siRNA, in most cases, have yet toovercome significant challenges such as drug delivery, absorption,distribution to target organs, pharmacokinetics, and cell penetration.In contrast, small molecules have a long history of successfullysurmounting these barriers and these qualities, which make them suitableas drugs, are readily optimized through a series of analogues toovercome such challenges. In sharp contrast, the application of smallmolecules as ligands for RNA that yield therapeutic benefit has receivedlittle to no attention from the drug discovery community.

DNA sequences in the chromosome are transcribed into pre-mRNAs whichcontain coding regions (exons) and generally also contain interveningnon-coding regions (introns). Introns are removed from pre-mRNAs throughsplicing. Pre-mRNA splicing proceeds by a two-step mechanism. In thefirst step, the 5′ splice site is cleaved, resulting in a “free” 5′ exonand a lariat intermediate. In the second step, the 5′ exon is ligated tothe 3′ exon with release of the intron as the lariat product. Thesesteps are catalyzed in a complex of small nuclear ribonucleoproteins andproteins called the spliceosome.

In most cases, the splicing reaction occurs within the same pre-mRNAmolecule, which is termed cis-splicing. Splicing between twoindependently transcribed pre-mRNAs is termed trans-splicing.

Introns are portions of eukaryotic DNA, which intervene between thecoding portions, or “exons,” of that DNA. Introns and exons aretranscribed into RNA termed “primary transcript, precursor to mRNA” (or“pre-mRNA”). Introns can be removed from the pre-mRNA so that the nativeprotein encoded by the exons can be produced (the term “native protein”as used herein refers to naturally occurring, wild type, or functionalprotein). The removal of introns from pre-mRNA and subsequent joining ofthe exons is carried out in the splicing process.

The splicing process is a series of reactions, which are carried out onRNA after transcription but before translation and which are mediated bysplicing factors. Thus, a “pre-mRNA” can be an RNA that contains bothexons and intron(s), and a mature mRNA (“mRNA”) can be an RNA in whichthe intron(s) have been removed and the exons joined togethersequentially so that the protein may be translated therefrom by theribosomes.

Introns can be defined by a set of “splice elements” that are part ofthe splicing machinery and may be required for splicing and which arerelatively short, conserved RNA segments that bind the various splicingfactors, which carry out the splicing reactions. Thus, each intron isdefined by a 5′ splice site, a 3′ splice site, and a branch pointsituated there between. Splice elements also comprise exon splicingenhancers and silencers, situated in exons, and intron splicingenhancers and silencers situated in introns at a distance from thesplice sites and branch points. In addition to splice site and branchpoints these elements control alternative aberrant and constitutivesplicing.

Initial RNA transcripts (pre-mRNA) of most eukaryotic genes are retainedin the nucleus until non-coding intron sequences are removed by thespliceosome to produce mature messenger RNA (mRNA). The splicing thatoccurs can vary, so the synthesis of alternative protein products fromthe same primary transcript can be affected by tissue-specific ordevelopmental signals. A significant fraction of human genetic diseases,including a number of cancers, are believed to result from deviations inthe normal pattern of pre-mRNA splicing. The spliceosome is a complexcomprising ribonucleoprotein (snRNP) particles composed of small nuclearRNAs and proteins. snRNA components of the spliceosome can promote thetwo transesterification reactions of splicing.

Two unique spliceosomes coexist in most eukaryotes: the U2-dependentspliceosome, which catalyzes the removal of U2-type introns, and theless abundant U12-dependent spliceosome, which is present in only asubset of eukaryotes and splices the rare U12-type class of introns. TheU2-dependent spliceosome is assembled from the U1, U2, U5, and U4/U6snRNPs and numerous non-snRNP proteins. The U2 snRNP is recruited withtwo weakly bound protein subunits, SF3a and SF3b, during the firstATP-dependent step in spliceosome assembly. SF3b is composed of sevenconserved proteins, including PHF5a, SF3b155, SF3b145, SF3b130, SF3b49,SF3b14a, and SF3b10.

Splicing or RNA splicing typically refers to the editing of the nascentprecursor messenger RNA (pre-mRNA) transcript into a mature messengerRNA (mRNA). Splicing is a biochemical process which includes the removalof introns followed by exon ligation. Sequential transesterificationreactions are initiated by a nucleophilic attack of the 5′ splice site(5′ss) by the branch adenosine (branch point; BP) in the downstreamintron resulting in the formation of an intron lariat intermediate witha 2′, 5′-phosphodiester linkage. This is followed by a 5′ss-mediatedattack on the 3′ splice site (3′ss), leading to the removal of theintron lariat and the formation of the spliced RNA product.

Splicing can be regulated by various cis-acting elements andtrans-acting factors. Cis-acting elements are sequences of the mRNA andcan include core consensus sequences and other regulatory elements. Coreconsensus sequences typically can refer to conserved RNA sequencemotifs, including the 5′ss, 3′ss, polypyrimidine tract and BP region,which can function for spliceosome recruitment. BP refers to a partiallyconserved sequence of pre-mRNA, generally less than 50 nucleotidesupstream of the 3′ss. BP reacts with the 5′ss during the first step ofthe splicing reaction. Other regulatory cis-acting elements can includeexonic splicing enhancer (ESE), exonic splicing silencer (ESS), intronicsplicing enhancer (ISE), and intronic splicing silencer (ISS).Trans-acting factors can be proteins or ribonucleoproteins which bind tocis-acting elements.

Splice site identification and regulated splicing can be accomplishedprincipally by two dynamic macromolecular machines, the major(U2-dependent) and minor (U12-dependent) spliceosomes. Each spliceosomecontains five snRNPs: U1, U2, U4, U5 and U6 snRNPs for the majorspliceosome (which processes ˜95.5% of all introns); and U11, U12,U4atac, U5 and U6 atac snRNPs for the minor spliceosome. Spliceosomerecognition of consensus sequence elements at the 5′ss, 3′ss and BPsites is one of the steps in the splicing pathway, and can be modulatedby ESEs, ISEs, ESSs, and ISSs, which can be recognized by auxiliarysplicing factors, including SR proteins and hnRNPs. Polypyrimidinetract-binding protein (PTBP) can bind to the polypyrimidine tract ofintrons and may promote RNA looping.

Alternative splicing is a mechanism by which a single gene mayeventually give rise to several different proteins. Alternative splicingcan be accomplished by the concerted action of a variety of differentproteins, termed “alternative splicing regulatory proteins,” thatassociate with the pre-mRNA, and cause distinct alternative exons to beincluded in the mature mRNA. These alternative forms of the gene'stranscript can give rise to distinct isoforms of the specified protein.Sequences in pre-mRNA molecules that can bind to alternative splicingregulatory proteins can be found in introns or exons, including, but notlimited to, ISS, ISE, ESS, ESE, and polypyrimidine tract. Many mutationscan alter splicing patterns. For example, mutations can be cis-actingelements, and can be located in core consensus sequences (e.g. 5′ss,3′ss and BP) or the regulatory elements that modulate spliceosomerecruitment, including ESE, ESS, ISE, and ISS.

A cryptic splice site, for example, a cryptic 5′ss and a cryptic 3′ss,can refer to a splice site that is not normally recognized by thespliceosome and therefore are in the dormant state. Cryptic splice sitecan be recognized or activated, for example, by mutations in cis-actingelements or trans-acting factors, or structural configurations, such asbulges.

Splicing Modulation

The present invention contemplates use of small molecules with favorabledrug properties that modulate the activity of splicing of a target RNA.Provided herein are small molecule splicing modulators (SMSMs) thatmodulate splicing of a target polynucleotide. In some embodiments, theSMSMs bind and modulate target RNA. In some embodiments, provided hereinis a library of SMSMs that bind and modulate one or more target RNAs. Insome embodiments, the target RNA is mRNA. In some embodiments, thetarget RNA is mRNA a noncoding RNA. In some embodiments, the target RNAis a pre-mRNA. In some embodiments, the target RNA is hnRNA. In someembodiments, the small molecules modulate splicing of the target RNA. Insome embodiments, a small molecule provided herein modulates splicing ata sequence of the target RNA. In some embodiments, a small moleculeprovided herein modulates splicing at a cryptic splice site sequence ofthe target RNA. In some embodiments, a small molecule provided hereinbinds to a target RNA. In some embodiments, a small molecule providedherein binds to a splicing complex component. In some embodiments, asmall molecule provided herein binds to a target RNA and a splicingcomplex component.

Thus, provided herein are methods of preventing or inducing a splicingevent in a pre-mRNA molecule, comprising contacting the pre-mRNAmolecule and/or other elements of the splicing machinery (e.g., within acell) with a compound provided herein to prevent or induce the splicingevent in the pre-mRNA molecule. The splicing event that is prevented orinduced can be, e.g., an aberrant splicing event, a constitutivesplicing event or an alternate splicing event.

Further provided herein is a method of identifying a compound capable ofpreventing or inducing a splicing event in a pre-mRNA molecule,comprising contacting the compound with splicing elements and/or factorsinvolved in alternative, aberrant and/or constitutive splicing asdescribed herein (e.g., within cells) under conditions whereby apositive (prevention or induction of splicing) or negative (noprevention or induction of splicing) effect is produced and detected andidentifying a compound that produces a positive effect as a compoundcapable of preventing or inducing a splicing event.

In some embodiments, a small molecule compound described herein in apharmaceutically acceptable carrier prevents or induces an alternativeor aberrant splicing event in a pre-mRNA molecule. As noted above, thesmall molecule compounds provided herein are not antisense or antigeneoligonucleotides. Table 1A, Table 1B and Table 1C show the chemicalstructure and name of exemplary compounds and is not intended to beall-inclusive.

In some embodiments, provided herein is a method of upregulatingexpression of a native protein in a cell containing a DNA encoding thenative protein, wherein the DNA contains a mutation or no mutation thatcauses downregulation of the native protein by aberrant and/or alternatesplicing thereof. For example, the DNA can encode a pre-mRNA that has amutation or an aberrant secondary or tertiary structure that causesdownregulation of one or more isoforms of a protein. The method cancomprise introducing into the cell a small molecule provided herein thatprevents an aberrant splicing event, whereby the native intron isremoved by correct splicing and the native protein is produced by thecell. In some embodiments, a method comprises introducing into a cell asmall molecule provided herein that modulates an alternate splicingevent to produce a protein that has a different function than theprotein that would be produced without modulation of alternate splicing.

In some embodiments, provided herein is a method of downregulatingexpression of a native protein in a cell containing a DNA encoding thenative protein, wherein the DNA contains a mutation or no mutation thatcauses upregulation of the native protein by aberrant and/or alternatesplicing thereof. For example, the DNA can encode a pre-mRNA that has amutation or an aberrant secondary or tertiary structure that causesupregulation of one or more isoforms of a protein. The method cancomprise introducing into the cell a small molecule provided herein thatprevents an aberrant splicing event, whereby the native intron isremoved by correct splicing and the native protein is produced by thecell. In some embodiments, a method comprises introducing into a cell asmall molecule provided herein that modulates an alternate splicingevent to produce a protein that has a different function than theprotein that would be produced without modulation of alternate splicing.For example, a method can comprise preventing aberrant splicing in apre-mRNA molecule containing a mutation or an aberrant secondary ortertiary structure and/or preventing an alternative splicing event. Whenpresent in the pre-mRNA, the mutation or aberrant secondary or tertiarystructure can cause a pre-mRNA to splice incorrectly and produce anaberrant mRNA or mRNA fragment different from the mRNA ordinarilyresulting from a pre-mRNA without the mutation or aberrant secondary ortertiary structure. For example, s pre-mRNA molecule can contain: (i) afirst set of splice elements defining a native intron which can beremoved by splicing when the mutation or aberrant secondary or tertiarystructure is absent to produce a first mRNA molecule encoding a nativeprotein, and (ii) a second set of splice elements induced by themutation or aberrant secondary or tertiary structure which defines anaberrant intron different from the native intron, which aberrant intronis removed by splicing when the mutation or aberrant secondary ortertiary structure is present to produce an aberrant second mRNAmolecule different from the first mRNA molecule. The method can comprisecontacting the pre-mRNA molecule and/or other factors and/or elements ofthe splicing machinery as described herein (e.g., within a cell) with acompound described herein to prevent or promote an aberrant splicingevent in a pre-mRNA molecule, whereby the native intron is removed bycorrect splicing and native protein production is increased in the cell.

Also provided herein is a method of upregulating expression of a RNAthat would otherwise be downregulated by modulating an alternativesplicing event in the RNA. The method can comprise contacting a pre-mRNAmolecule and/or other elements and/or factors of the splicing machinerywith a compound described herein to modulate alternate splicing events,whereby a native splicing event is inhibited and an alternate splicingevent is promoted that upregulates expression of a RNA that is otherwisedownregulated when under the control of the native splicing event.

Also provided herein is a method of downregulating expression of a RNAthat would otherwise be upregulated by modulating an alternativesplicing event in the RNA. The method can comprise contacting a pre-mRNAmolecule and/or other elements and/or factors of the splicing machinerywith a compound described herein to modulate alternate splicing events,whereby a native splicing event is inhibited and an alternate splicingevent is promoted that downregulates expression of a RNA that isotherwise upregulated when under the control of the native splicingevent.

The methods, compounds and compositions described herein have a varietyof uses. For example, they are useful in any process where it is desiredto have a means for downregulating expression of a RNA to be expresseduntil a certain time, after which it is desired to upregulate RNAexpression. For such use, the RNA to be expressed may be any RNAencoding a protein to be produced so long as the gene contains a nativeintron. The RNA may be mutated by any suitable means, such assite-specific mutagenesis (see, T. Kunkel, U.S. Pat. No. 4,873,192) todeliberately create an aberrant second set of splice elements whichdefine an aberrant intron which substantially downregulates expressionof the gene. A sequence encoding the RNA may be inserted into a suitableexpression vector and the expression vector inserted into a host cell(e.g., a eukaryotic cell such as a yeast, insect, or mammalian cell(e.g., human, rat)) by standard recombinant techniques. The host cellcan then be grown in culture by standard techniques. When it is desiredto upregulate expression of the mutated gene, a suitable compound of thepresent invention, in a suitable formulation, can be added to theculture medium so that expression of the gene is upregulated.

Also provided herein is a method of altering the ratio of splicevariants produced from a gene. The method can comprise contacting apre-mRNA molecule and/or other elements and/or factors of the splicingmachinery with a compound or compounds described herein to modulatealternative splicing events. The compound or compounds of this inventioncan be used to act upon 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 alternative splicing events that may occurwithin a pre-mRNA. In some embodiments, a first splice variant may bedownregulated or inhibited and/or a second splice variant may beupregulated, resulting in an altered ratio of splice variants of the twoor more RNA. In some embodiments, a first splice variant may beupregulated while a second splice variant may be unaffected, therebyaltering the ratio of the RNA. In some embodiments, a first splicevariant may be downregulated while a second splicing event may beunaffected thereby altering the ratio of the RNA.

The methods, compounds and formulations described herein are also usefulas in vitro or in vivo tools to examine and modulate splicing events inhuman or animal RNAs encoded by genes, e.g., those developmentallyand/or tissue regulated (e.g., alternate splicing events).

The compounds and formulations described herein are also useful astherapeutic agents in the treatment of disease involving aberrant and/oralternate splicing. Thus, in some embodiments, a method of treating asubject having a condition or disorder associated with an alternative oraberrant splicing event in a pre-mRNA molecule, comprises administeringto the subject a therapeutically effective amount of a compounddescribed herein to modulate an alternative splicing event or prevent anaberrant splicing event, thereby treating the subject. The method can,e.g., restore a correct splicing event in a pre-mRNA molecule. Themethod can, e.g., utilize a small molecule compound described herein ina pharmaceutically acceptable carrier.

Formulations containing the small molecules described herein cancomprise a physiologically or pharmaceutically acceptable carrier, suchas an aqueous carrier. Thus, formulations for use in the methodsdescribed herein include, but are not limited to, those suitable fororal administration, parenteral administration, including subcutaneous,intradermal, intramuscular, intravenous and intra-arterialadministration, as well as topical administration (e.g., administrationof an aerosolized formulation of respirable particles to the lungs of apatient afflicted with cystic fibrosis or lung cancer or a cream orlotion formulation for transdermal administration of patients withpsoriasis). The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart. The most suitable route of administration in any given case maydepend upon the subject, the nature and severity of the condition beingtreated, and the particular active compound, which is being used, aswould be readily determined by one of skill in the art.

Also provided herein are methods for the use of a compound describedherein having the characteristics set forth above for the preparation ofa medicament for upregulating or downregulating RNA expression in apatient having a disorder associated with aberrant or alternate splicingof a pre-mRNA molecule, as discussed above. In some embodiments, themedicament upregulates gene expression. In other embodiments, themedicament downregulates gene expression. In the manufacture of atmedicament according to the invention, the compound can be admixed with,inter alia, a pharmaceutically acceptable carrier. The carrier may be asolid or a liquid. One or more compounds may be incorporated in anycombination in the formulations described herein, which may be preparedby any of the well-known techniques of pharmacy, such as admixing thecomponents, and/or including one or more accessory therapeuticingredients.

The present inventors identify herein low molecular weight compounds(sometimes referred to herein as small molecules, which block mRNAsplicing and/or enhance (facilitate, augment) mRNA splicing. Thesplicing that can be regulated by the methods described herein includealternative splicing, e.g., exon skipping, intron retention, pseudoexonsskipping, exon exclusion, partial intron exclusion and others. Dependingon factors such as the splicing sequence and the RNA (or gene encodingthe RNA) or exon involved, modulation of splicing can be accomplished inthe presence of, or in the absence of, antisense oligonucleotides (AOs)that are specific for splicing sequences of interest. In someembodiments, a small molecule and an AO act synergistically.

In some aspects, a method comprises contacting a splice modulatingcompound (e.g., a SMSM) to a pre-mRNA that modulates splicing of thepre-mRNA to favor expression of a transcript that promotes cellproliferation. For example, an SMSM described herein can increase one ormore isoforms of a transcript that promotes cell proliferation. Forexample, an SMSM described herein can decrease expression one or moreisoforms of a transcript that prevents or inhibits cell proliferation.

In some aspects, a method comprises contacting a splice modulatingcompound (e.g., a SMSM) to a pre-mRNA that modulates splicing of thepre-mRNA to favor expression of a transcript that prevents or inhibitscell proliferation. For example, an SMSM described herein can increaseone or more isoforms of a transcript that prevents or inhibits cellproliferation. For example, an SMSM described herein can decreaseexpression one or more isoforms of a transcript that promotes cellproliferation.

In some embodiments, a method of modulating splicing of pre-mRNAcomprises using an SMSM to decrease expression or functionality of oneor more isoforms of a transcript in a subject. The method can compriseadministering an SMSM, or a composition comprising an SMSM, to asubject, wherein the SMSM binds to a pre-mRNA or a splicing complexcomponent and modulates splicing of the pre-mRNA to favor expression ofone or more isoforms of a transcript. The method can compriseadministering an SMSM, or a composition comprising an SMSM, to asubject, wherein the SMSM binds to a pre-mRNA or a splicing complexcomponent and modulates splicing of the pre-mRNA to disfavor expressionof one or more isoforms of a transcript.

In some embodiments, the present invention provides a method of treatinga subject afflicted with a disease or condition associated with aberrantsplicing of a pre-mRNA. The method can comprise administering an SMSM,or a composition comprising an SMSM, to a subject, wherein the SMSMbinds to a pre-mRNA or a splicing complex component and modulatessplicing of the pre-mRNA to inhibit expression of one or more isoformsof a transcript. The method can comprise administering an SMSM, or acomposition comprising an SMSM, to a subject, wherein the SMSM binds toa pre-mRNA or a splicing complex component and modulates the splicing ofthe pre-mRNA to increase expression of one or more isoforms of atranscript.

A number of diseases are associated with expression of an aberrant geneproduct (e.g., an RNA transcript or protein) of a gene. For example,aberrant amounts of a RNA transcript may lead to disease due tocorresponding changes in protein expression. Changes in the amount of aparticular RNA transcript may be the result of several factors. First,changes in the amount of RNA transcripts may be due to an aberrant levelof transcription of a particular gene, such as by the perturbation of atranscription factor or a portion of the transcription process,resulting in a change in the expression level of a particular RNAtranscript. Second, changes in the splicing of particular RNAtranscripts, such as by perturbation of a particular splicing process ormutations in the gene that lead to modified splicing can change thelevels of a particular RNA transcript.

Changes to the stability of a particular RNA transcript or to componentsthat maintain RNA transcript stability, such as the process of poly-Atail incorporation or an effect on certain factors or proteins that bindto and stabilize RNA transcripts, may lead to changes in the levels of aparticular RNA transcript. The level of translation of particular RNAtranscripts can also affect the amount of those transcripts, affectingor upregulating RNA transcript decay processes. Finally, aberrant RNAtransport or RNA sequestration may also lead to changes in functionallevels of RNA transcripts, and may have an effect on the stability,further processing, or translation of the RNA transcripts.

In some embodiments, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts encoded by a pre-mRNA,comprising contacting a cell with an SMSM compound or a pharmaceuticallyacceptable salt thereof. In some embodiments, the cell is contacted withan SMSM compound or a pharmaceutically acceptable salt thereof in a cellculture. In other embodiments, the cell is contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof in a subject(e.g., a non-human animal subject or a human subject).

In some embodiments, provided herein are methods for treatment,prevention and/or delay of progression of a disease or conditioncomprising administering an effective amount of a small moleculesplicing modulator as described herein to a subject, in particular to amammal.

In some embodiments, provided herein are compositions and methods fortreating a disease or condition, including steric modulator compounds orpharmaceutically acceptable salts thereof that promote prevention orcorrection of exon skipping of a pre-mRNA. The invention furtherprovides compositions and methods for increasing production of maturemRNA and, in turn, protein, in cells of a subject in need thereof, forexample, a subject that can benefit from increased production ofprotein. The invention further provides compositions and methods fordecreasing production of mature mRNA and, in turn, protein, in cells ofa subject in need thereof, for example, a subject that can benefit fromdecreased production of protein. In one embodiment, the describedmethods may be used to treat subjects having a disease or conditioncaused by a mutation in a gene, including missense, splicing, frameshiftand nonsense mutations, as well as whole gene deletions, which result indeficient protein production. In another embodiment, the describedmethods may be used to treat subjects having a disease or condition notcaused by gene mutation. In some embodiments, the compositions andmethods of the present invention are used to treat subjects having adisease or condition, who can benefit from increased production ofprotein. In some embodiments, the compositions and methods of thepresent invention are used to treat subjects having a disease orcondition, who can benefit from increased production of protein. In someembodiments, the compositions and methods of the present invention areused to treat subjects having a disease or condition, who can benefitfrom decreased production of a protein.

In some embodiments, provided herein are methods of treating a diseaseor condition in a subject in need thereof by increasing the expressionof a target protein or functional RNA by cells of the subject, whereinthe cells have a mutation that causes, e.g., exon skipping or introninclusion, or a portion thereof, of pre-mRNA, wherein the pre-mRNAencodes the target protein or functional RNA. The method can comprisecontacting cells of a subject with an SMSM compound or apharmaceutically acceptable salt thereof that targets the pre-mRNAencoding the target protein or functional RNA or splicing complexcomponent, whereby splicing of an exon from a pre-mRNA encoding a targetprotein or functional RNA is prevented or inhibited, thereby increasinga level of mRNA encoding the target protein or functional RNA, andincreasing the expression of the target protein or functional RNA in thecells of the subject. In some embodiments, also disclosed herein is amethod of increasing expression of a target protein by cells having amutation or aberrant secondary or tertiary RNA structure that causesexon skipping of pre-mRNA, the pre-mRNA comprising a mutation oraberrant secondary or tertiary RNA structure that causes exon skipping.The method can comprise contacting the cells with an SMSM compound or apharmaceutically acceptable salt thereof that targets a pre-mRNAencoding a target protein or functional RNA, whereby splicing of an exonfrom a pre-mRNA encoding a target protein or functional RNA is preventedor inhibited, thereby increasing the level of mRNA encoding functionalprotein, and increasing the expression of protein in the cells. In someembodiments, the target protein is a tumor suppressor. In someembodiments, the target protein is a tumor promoter. In someembodiments, the target protein or the functional RNA is a compensatingprotein or a compensating functional RNA that functionally augments orreplaces a target protein or functional RNA that is deficient in amountor activity in the subject. In some embodiments, the cells are in orfrom a subject having a condition caused by a deficient amount oractivity of the protein. In some embodiments, the deficient amount ofthe target protein is caused by haploinsufficiency of the targetprotein, wherein the subject has a first allele encoding a functionaltarget protein, and a second allele from which the target protein is notproduced, or a second allele encoding a nonfunctional target protein,and wherein an SMSM compound or a pharmaceutically acceptable saltthereof binds to a targeted portion of a pre-mRNA transcribed from thefirst allele. In some embodiments, the target protein is produced in aform that is fully-functional compared to the equivalent proteinproduced from mRNA in which an exon has been skipped or is missing. Insome embodiments, the pre-mRNA is encoded by a genetic sequence with atleast about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequenceidentity to a pre-mRNA. In some embodiments, an SMSM compound or apharmaceutically acceptable salt thereof increases the amount of thetarget protein or the functional RNA by modulating alternative splicingof pre-mRNA transcribed from a gene encoding the functional RNA ortarget protein. In some embodiments, an SMSM compound or apharmaceutically acceptable salt thereof increases the amount of thetarget protein or the functional RNA by modulating aberrant splicingresulting from mutation of the gene encoding the target protein or thefunctional RNA.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increased atleast about 10%, at least about 20%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 100%, at least about 150%, at least about 200%, at leastabout 250%, at least about 300%, at least about 400%, or at least about500%, compared to the total amount of the mRNA encoding the targetprotein or functional RNA produced in a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with than SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, or about 200% to about 250%, compared tothe total amount of the mRNA encoding the target protein or functionalRNA produced in a control cell.

In some embodiments, the total amount of target protein produced by thecell contacted with an SMSMS compound or a pharmaceutically acceptablesalt thereof is increased at least about 20%, at least about 50%, atleast about 100%, at least about 150%, at least about 200%, at leastabout 250%, or at least about 300%, compared to the total amount oftarget protein produced by a control cell. In some embodiments, thetotal amount of target protein produced by the cell contacted with anSMSM compound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, or about 200% to about 250%, compared tothe total amount of target protein produced by a control cell.

In some embodiments, a total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increased atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-foldcompared to the total amount of the mRNA encoding the target protein orfunctional RNA produced in a control cell. In some embodiments, a totalamount of an mRNA encoding the target protein or functional RNA producedin a cell contacted with an SMSM compound or a pharmaceuticallyacceptable salt thereof is increased about 1.1 to about 10-fold, about1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold,about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 toabout 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about4 to about 8-fold, or about 4 to about 9-fold, compared to a totalamount of the mRNA encoding the target protein or functional RNAproduced in a control cell.

In some embodiments, a total amount of target protein produced by a cellcontacted with an SMSM compound or a pharmaceutically acceptable saltthereof is increased at least about 1.1-fold, at least about 1.5-fold,at least about 2-fold, at least about 2.5-fold, at least about 3-fold,at least about 3.5-fold, at least about 4-fold, at least about 5-fold,or at least about 10-fold, compared to the total amount of targetprotein produced by a control cell. In some embodiments, the totalamount of target protein produced by the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, or about 4 to about 9-fold,compared to a total amount of target protein produced by a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreased atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, or at least about 100%, compared tothe total amount of the mRNA encoding the target protein or functionalRNA produced in a control cell.

In some embodiments, the total amount of the mRNA encoding the targetprotein or functional RNA produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100% about 90%to about 100%, about 20% to about 30%, about 20% to about 40%, about 20%to about 50%, about 20% to about 60%, about 20% to about 70%, about 20%to about 80%, about 20% to about 90%, about 30% to about 40%, about 30%to about 50%, about 30% to about 60%, about 30% to about 70%, about 30%to about 80%, about 30% to about 90%, about 40% to about 50%, about 40%to about 60%, about 40% to about 70%, about 40% to about 80%, about 40%to about 90%, about 50% to about 60%, about 50% to about 70%, about 50%to about 80%, about 50% to about 90%, about 60% to about 70%, about 60%to about 80%, about 60% to about 90%, 70% to about 80%, about 70% toabout 90%, or about 80% to about 90%, compared to the total amount ofthe mRNA encoding the target protein or functional RNA produced in acontrol cell.

In some embodiments, the total amount of target protein produced by thecell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is decreased at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, or atleast about 100%, compared to the total amount of target proteinproduced by a control cell. In some embodiments, the total amount oftarget protein produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is decreased about 10% to about100%, about 20% to about 100%, about 30% to about 100%, about 40% toabout 100%, about 50% to about 100%, about 60% to about 100%, about 70%to about 100%, about 80% to about 100% about 90% to about 100%, about20% to about 30%, about 20% to about 40%, about 20% to about 50%, about20% to about 60%, about 20% to about 70%, about 20% to about 80%, about20% to about 90%, about 30% to about 40%, about 30% to about 50%, about30% to about 60%, about 30% to about 70%, about 30% to about 80%, about30% to about 90%, about 40% to about 50%, about 40% to about 60%, about40% to about 70%, about 40% to about 80%, about 40% to about 90%, about50% to about 60%, about 50% to about 70%, about 50% to about 80%, about50% to about 90%, about 60% to about 70%, about 60% to about 80%, about60% to about 90%, 70% to about 80%, about 70% to about 90%, or about 80%to about 90%, compared to the total amount of target protein produced bya control cell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, about 200% to about 250%, at least about20%, at least about 50%, at least about 100%, at least about 150%, atleast about 200%, at least about 250%, or at least about 300%, comparedto the difference in amounts between the two splice variants produced bya control cell. In some embodiments, the difference in amount between afirst protein isoform expressed from a first splice variant and a secondprotein isoform expressed from a second splice variant produced by thecell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is increased about 20% to about 300%, about 50% to about300%, about 100% to about 300%, about 150% to about 300%, about 20% toabout 50%, about 20% to about 100%, about 20% to about 150%, about 20%to about 200%, about 20% to about 250%, about 50% to about 100%, about50% to about 150%, about 50% to about 200%, about 50% to about 250%,about 100% to about 150%, about 100% to about 200%, about 100% to about250%, about 150% to about 200%, about 150% to about 250%, about 200% toabout 250%, at least about 20%, at least about 50%, at least about 100%,at least about 150%, at least about 200%, at least about 250%, or atleast about 300%, compared to the difference in amounts between twoprotein isoforms produced from the splice variants produced by a controlcell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is increasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-fold,compared to the difference in amounts between the two splice variantsproduced by a control cell. In some embodiments, the difference inamount between a first protein isoform expressed from a first splicevariant and a second protein isoform expressed from a second splicevariant produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is increased about 1.1 to about10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold,about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 toabout 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold,about 4 to about 8-fold, about 4 to about 9-fold, at least about1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about4-fold, at least about 5-fold, or at least about 10-fold, compared tothe difference in amounts between two protein isoforms expressed fromthe splice variants produced by a control cell.

In some embodiments, a difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in a cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 20% to about 300%, about 50% to about 300%, about 100% to about300%, about 150% to about 300%, about 20% to about 50%, about 20% toabout 100%, about 20% to about 150%, about 20% to about 200%, about 20%to about 250%, about 50% to about 100%, about 50% to about 150%, about50% to about 200%, about 50% to about 250%, about 100% to about 150%,about 100% to about 200%, about 100% to about 250%, about 150% to about200%, about 150% to about 250%, about 200% to about 250%, at least about20%, at least about 50%, at least about 100%, at least about 150%, atleast about 200%, at least about 250%, or at least about 300%, comparedto the difference in amounts between the two splice variants produced bya control cell. In some embodiments, a difference in amount between afirst protein isoform expressed from a first splice variant and a secondprotein isoform expressed from a second splice variant produced by acell contacted with an SMSM compound or a pharmaceutically acceptablesalt thereof is decreased about 20% to about 300%, about 50% to about300%, about 100% to about 300%, about 150% to about 300%, about 20% toabout 50%, about 20% to about 100%, about 20% to about 150%, about 20%to about 200%, about 20% to about 250%, about 50% to about 100%, about50% to about 150%, about 50% to about 200%, about 50% to about 250%,about 100% to about 150%, about 100% to about 200%, about 100% to about250%, about 150% to about 200%, about 150% to about 250%, about 200% toabout 250%, at least about 20%, at least about 50%, at least about 100%,at least about 150%, at least about 200%, at least about 250%, or atleast about 300%, compared to a difference in amounts between twoprotein isoforms produced from the splice variants produced by a controlcell.

In some embodiments, the difference in amount between a first splicevariant and a second splice variant encoding a target protein orfunctional RNA isoform produced in the cell contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof is decreasedabout 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold,about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 toabout 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, atleast about 1.1-fold, at least about 1.5-fold, at least about 2-fold, atleast about 2.5-fold, at least about 3-fold, at least about 3.5-fold, atleast about 4-fold, at least about 5-fold, or at least about 10-fold,compared to the difference in amounts between the two splice variantsproduced by a control cell. In some embodiments, the difference inamount between a first protein isoform expressed from a first splicevariant and a second protein isoform expressed from a second splicevariant produced by the cell contacted with an SMSM compound or apharmaceutically acceptable salt thereof is decreased about 1.1 to about10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold,about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 toabout 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold,about 4 to about 8-fold, about 4 to about 9-fold, at least about1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about4-fold, at least about 5-fold, or at least about 10-fold, compared tothe difference in amounts between two protein isoforms express from thesplice variants produced by a control cell.

The ratio of a first isoform and a second isoform may contribute to anumber of conditions or diseases. In some embodiments, a subject withouta condition or disease has a first isoform to second isoform ratio of1:1. In some embodiments, a subject with a condition or diseasedescribed herein has a first isoform to second isoform ratio of about1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.In some embodiments, a subject with a condition or disease describedherein has a first isoform to second isoform ratio from about 1:1 toabout 1:1.1, about 1:1 to about 1:1.2, about 1:1 to about 1:1.3, about1:1 to about 1:1.4, about 1:1 to about 1:1.5, about 1:1 to about 1:1.6,about 1:1 to about 1:1.8, about 1:1 to about 1:2, about 1:1 to about1:3, about 1:1 to about 1:3.5, about 1:1 to about 1:4, about 1:1 toabout 1:4.5, about 1:1 to about 1:5, 1:2 to about 1:3, about 1:2 toabout 1:4, about 1:2 to about 1:5, about 1:3 to about 1:4, about 1:3 toabout 1:5, or about 1:4 to about 1:5.

In some embodiments, binding of an SMSM compound or a pharmaceuticallyacceptable salt thereof to pre-mRNA prevents splicing out of one or moreexons and/or introns and/or proteins thereof, from the population ofpre-mRNAs to produce mRNA encoding the target protein or functional RNA.In some embodiments, the cell comprises a population of pre-mRNAstranscribed from the gene encoding the target protein or functional RNA,wherein the population of pre-mRNAs comprises a mutation that causes thesplicing out of one or more exons, and wherein an SMSM compound or apharmaceutically acceptable salt thereof binds to the mutation thatcauses the splicing out of the one or more exons in the population ofpre-mRNAs. In some embodiments, the binding of an SMSM compound or apharmaceutically acceptable salt thereof to the mutation that causes thesplicing out of the one or more exons prevents splicing out of the oneor more exons from the population of pre-mRNAs to produce mRNA encodingthe target protein or functional RNA. In some embodiments, the conditionis a disease or disorder. In some embodiments, the method furthercomprises assessing protein expression. In some embodiments, an SMSMcompound or a pharmaceutically acceptable salt thereof binds to atargeted portion of a pre-mRNA.

In some embodiments, the binding of an SMSM compound or apharmaceutically acceptable salt thereof catalyzes the inclusion of amissing exon or removal of an undesired retained intron or portionsthereof, resulting in healthy mRNA and proteins. In some embodiments,the binding of an SMSM compound or a pharmaceutically acceptable saltthereof has minimal to no effect on non-diseased cells.

In some embodiments, an SMSM kills cells at an IC₅₀ of less than 50 nM.In some embodiments, the cells are primary cells. In some embodiments,an SMSM kills the cells at an IC₅₀ of less than 48 nM, 45 nM, 40 nM, 35nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 3 nM, or 1 nM.

In some embodiments, an SMSM modulates splicing at a splice sitesequence of a polynucleotide of the primary cells. In some embodiments,an SMSM modulates proliferation or survival of the primary cells. Insome embodiments, the primary cells are primary diseased cells. In someembodiments, the primary diseased cells are primary cancer cells. Insome embodiments, the SMSM is present at a concentration of at leastabout 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1 mM, 10 mM, 100 mM, or1 M. In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%,60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primarydiseased cells are killed. In some embodiments, at least about 5%, 10%,25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or100% of the primary diseased cells undergo apoptosis.

In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%,70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primarydiseased cells undergo necrosis. In some embodiments, proliferation isreduced or inhibited in at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%,70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% of the primarydiseased cells. In some embodiments, the primary diseased cells arenon-transformed cells.

In some embodiments, an SMSM reduces a size of a tumor in a subject. Insome embodiments, a size of a tumor in a subject administered an SMSM ora pharmaceutically acceptable salt thereof is reduced by at least about1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% in the subject. In someembodiments, a diameter of a tumor in a subject administered an SMSM ora pharmaceutically acceptable salt thereof is reduced by at least about1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a volumeof the tumor is reduced by at least about 1%, 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%,97%, 98%, or 99% in the subject. In some embodiments, the tumor ismalignant.

In some embodiments, a method comprises contacting an SMSM to primarynon-diseased cells. In some embodiments, at most about 1%, 5%, 10%, 15%,20%, 25%, or 50% of the primary non-diseased cells are killed.

In some embodiments, at most about 1%, 5%, 10%, 15%, 20%, 25%, or 50% ofthe primary non-diseased cells undergo apoptosis. In some embodiments,at most about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primarynon-diseased cells undergo necrosis. In some embodiments, proliferationis reduced or inhibited in at most about 1%, 5%, 10%, 15%, 20%, 25%, or50% of the primary non-diseased cells. In some embodiments, the primarynon-diseased cells are of the same tissue as the primary diseased cells.In some embodiments, the primary non-diseased cells are differentiatedcells.

An SMSM can modulate splicing at a splice site of a polynucleotide anddoes not exhibit significant toxicity. In some embodiments, an SMSMpenetrates the blood brain barrier (BBB) when administered to a subject.

In some embodiments, an SMSM has a brain/blood AUC of at least about0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 40, or higher.

In some embodiments, an SMSM has a half-life of at least about 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160,170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375,400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or1000 hours in a human.

In some embodiments, an SMSM is stable at room temperature for at least1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23 or 24 hours; or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 months; or at least 1, 2, 3, 4, or 5 years. In some embodiments,an SMSM is stable at 4° C. for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours; or forat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months; or at least 1,2, 3, 4, or 5 years. In some embodiments, an SMSM is stable at roomtemperature in water or an organic solvent for at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24hours; or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months; orat least 1, 2, 3, 4, or 5 years. In some embodiments, an SMSM is stableat 4° C. in water or an organic solvent for at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24hours; or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months;or at least 1, 2, 3, 4, or 5 years.

In some embodiments, an SMSM has an cell viability IC₅₀ of 0.01-10 nM,0.01-5 nM, 0.01-2.5 nM, 0.01-1 nM, 0.01-0.75 nM, 0.01-0.5 nM, 0.01-0.25nM, 0.01-0.1 nM, 0.1-100 nM, 0.1-50 nM, 0.1-25 nM, 0.1-10 nM, 0.1-7.5nM, 0.1-5 nM, 0.1-2.5 nM, 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75nM, 2-50 nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100nM, 10-75 nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM,25-100 nM, 25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100nM, 50-75 nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000nM, 250-500 nM, or 500-1000 nM.

In some embodiments, an SMSM has an cell viability IC₅₀ of at most 2 nM,3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81 nM, 82 nM, 83 nM, 84nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM,160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM,250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM,475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,900 nM, 950 nM, 1 μM, or 10 μM.

In some embodiments, an SMSM reduces cell proliferation of diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% when thecells are treated with the SMSM at a concentration of 2-1000 nM, 2-500nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50 nM, 2-25 nM, 2-10 nM, 10-1000 nM,10-500 nM, 10-250 nM, 10-100 nM, 10-75 nM, 10-50 nM, 10-25 nM, 25-1000nM, 25-500 nM, 25-250 nM, 25-100 nM, 25-75 nM, 25-50 nM, 50-1000 nM,50-500 nM, 50-250 nM, 50-100 nM, 50-75 nM, 60-70 nM, 100-1000 nM,100-500 nM, 100-250 nM, 250-1000 nM, 250-500 nM, or 500-1000 nM for atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM reduces cell proliferation of diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% when thecells are treated with the SMSM at a concentration of at least 2 nM, 3nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81 nM, 82 nM, 83 nM, 84nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM,160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM,250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM,475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,900 nM, 950 nM, 1 μM, or 10 μM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, or 48 hours.

In some embodiments, an SMSM reduces viability of diseased cells by morethan 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100%. when the cells are treated with the SMSM at aconcentration of 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100 nM, 10-75nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM, 25-100 nM,25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100 nM, 50-75nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000 nM, 250-500nM, or 500-1000 nM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or48 hours.

In some embodiments, an SMSM reduces viability of diseased cells by morethan 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100% when the cells are treated with the SMSM at a concentrationof at least 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21nM, 22 nM, 23 nM, 24 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 51nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81nM, 82 nM, 83 nM, 84 nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM,130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM,220 nM, 230 nM, 240 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM,400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM,750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, or 10 μM for at least1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM does not reduce viability of non-diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, or 50 when the cells are treated with the SMSM at aconcentration of 2-1000 nM, 2-500 nM, 2-250 nM, 2-100 nM, 2-75 nM, 2-50nM, 2-25 nM, 2-10 nM, 10-1000 nM, 10-500 nM, 10-250 nM, 10-100 nM, 10-75nM, 10-50 nM, 10-25 nM, 25-1000 nM, 25-500 nM, 25-250 nM, 25-100 nM,25-75 nM, 25-50 nM, 50-1000 nM, 50-500 nM, 50-250 nM, 50-100 nM, 50-75nM, 60-70 nM, 100-1000 nM, 100-500 nM, 100-250 nM, 250-1000 nM, 250-500nM, or 500-1000 nM for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,21, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or48 hours.

In some embodiments, an SMSM does not reduce viability of non-diseasedcells by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%,35%, 40%, 45%, or 50% when the cells are treated with the SMSM at aconcentration of at least 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45nM, 50 nM, 51 nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59nM, 60 nM, 61 nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69nM, 70 nM, 71 nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79nM, 80 nM, 81 nM, 82 nM, 83 nM, 84 nM, 85 nM, 90 nM, 95 nM, 100 nM, 110nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, or 10 μM forat least 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours.

In some embodiments, an SMSM reduces a size of a tumor in a subject byat least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%,66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%,80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or 100%.

In some embodiments, an SMSM inhibits tumor growth of a tumor in asubject by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%,50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

SMSM Targets

Aberrant splicing of mRNA, such as pre-mRNA, can result in a defectiveprotein and can cause a disease or a disorder in a subject. Thecompositions and methods described herein can reduce this aberrantsplicing of mRNA, such as pre-mRNA, and treat a disease or a disordercaused by this aberrant splicing.

Diseases associated with changes to RNA transcript amount are oftentreated with a focus on the aberrant protein expression. However, if theprocesses responsible for the aberrant changes in RNA levels, such ascomponents of the splicing process or associated transcription factorsor associated stability factors, could be targeted by treatment with asmall molecule, it would be possible to restore protein expressionlevels such that the unwanted effects of the expression of aberrantlevels of RNA transcripts or associated proteins. Therefore, there is aneed for methods of modulating the amount of RNA transcripts encoded bycertain genes as a way to prevent or treat diseases associated withaberrant expression of the RNA transcripts or associated proteins.

Structural Targets

Mutations and/or aberrant secondary or tertiary RNA structures incis-acting elements can induce three-dimensional structural change inpre-mRNA. Mutations and/or aberrant secondary RNA structures incis-acting elements can induce three-dimensional structural change inpre-mRNA when the pre-mRNA is, for example, bound to at least one snRNA,or at least one snRNP, or at least one other auxiliary splicing factor.For example, non-canonical base pairing of a non-canonical splice sitesequence to a snRNA can form a bulge. For example, a bulge can be formedwhen the 5′ss is bound to U1-U12 snRNA or a portion thereof. Forexample, a bulge can be induced to form when 5′ss containing at leastone mutation is bound to U1-U12 snRNA or a portion thereof. For example,a bulge can be formed when the cryptic 5′ss is bound to U1-U12 snRNA ora portion thereof. For example, a bulge can be induced to form whencryptic 5′ss containing at least one mutation is bound to U1-U12 snRNAor a portion thereof. For example, a bulge can be formed when the 3′ssis bound to U2 snRNA or a portion thereof. For example, a bulge can beinduced to form when the 3′ss is bound to U2 snRNA or a portion thereof.For example, a bulge can be formed when the cryptic 3′ss is bound to U2snRNA or a portion thereof. For example, a bulge can be induced to formwhen the cryptic 3′ss is bound to U2 snRNA or a portion thereof. Theprotein components of U1 and U2 may or may not present to form thebulge. Exemplary 5′ splice site mutations and/or with aberrant secondaryand/or tertiary structures that can induce a bulge structure are shownin Table 2A, Table 2B, Table 2C and Table 2D. A polynucleotide in themethods disclosed herein can contain any one of exemplary the 5′ splicesite sequences summarized in Table 2A, Table 2B, Table 2C and Table 2D.

In some embodiments, a small molecule can bind to a bulge. In someembodiments, a bulge is naturally occurring. In some embodiments, abulge is formed by non-canonical base-pairing between the splice siteand the small nuclear RNA. For example, a bulge can be formed bynon-canonical base-pairing between the 5′ss and U1-U12 snRNA. The bulgecan comprise 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides,5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13nucleotides, 14 nucleotides, or 15 nucleotides. In some embodiments,3-dimensional structural changes can be induced by a mutation withoutbulge formation. In some embodiments, a bulge may be formed without anymutation in a splice site. In some embodiments, a recognition portioncan be formed by a mutation in any of the cis-acting elements. In someembodiments, a small molecule can bind to a recognition portion that isinduced by a mutation. In some embodiments, a mutation and/or aberrantsecondary or tertiary RNA structure at an authentic 5′ splice site canresult in splicing at a cryptic 5′ splice site. In some embodiments, amutation and/or aberrant secondary or tertiary RNA structure can be inone of the regulatory elements including ESEs, ESSs, ISEs, and ISSs.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide in an exon. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide upstream (5′) of the splice site ofthe splice site sequence. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe −1 position relative to the splice site of the splice site sequence.For example, a target of an SMSM can be a pre-mRNA comprising a splicesite sequence of NNN*nnnnnn, wherin N* represents a bulged nucleotide.In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the −2 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNN*Nnnnnnn, wherin N* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the −3 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of N*NNnnnnnn,wherin N* represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide in an intron. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide downstream (3′) of the splice site ofthe splice site sequence.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the +1 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNNNn*nnnnn, wherin n* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the +2 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of NNNnn*nnnn,wherin n* represents a bulged nucleotide. In some embodiments, a targetof an SMSM is a pre-mRNA comprising a splice site sequence with a bulgednucleotide at the +3 position relative to the splice site of the splicesite sequence.

For example, a target of an SMSM can be a pre-mRNA comprising a splicesite sequence of NNNnnn*nnn, wherin n* represents a bulged nucleotide.In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the +4 positionrelative to the splice site of the splice site sequence. For example, atarget of an SMSM can be a pre-mRNA comprising a splice site sequence ofNNNnnnn*nn, wherin n* represents a bulged nucleotide. In someembodiments, a target of an SMSM is a pre-mRNA comprising a splice sitesequence with a bulged nucleotide at the +5 position relative to thesplice site of the splice site sequence. For example, a target of anSMSM can be a pre-mRNA comprising a splice site sequence of NNNnnnnn*n,wherin n* represents a bulged nucleotide. In some embodiments, a targetof an SMSM is a pre-mRNA comprising a splice site sequence with a bulgednucleotide at the +6 position relative to the splice site of the splicesite sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NNNnnnnnn*, wherin n* represents abulged nucleotide. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe +7 position relative to the splice site of the splice site sequence.For example, a target of an SMSM can be a pre-mRNA comprising a splicesite sequence of NNNnnnnnnn*, wherin n* represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the −1, −2,−3, +1, +2, +3, +4, +5, +6 and/or +7 position relative to the splicesite of the splice site sequence. For example, a target of an SMSM canbe a pre-mRNA comprising a splice site sequence of NNN*nnnnnn,NN*Nnnnnnn, N*NNnnnnnn, NNNn*nnnnn, NNNnn*nnnn, NNNnnn*nnn, NNNnnnn*nn,NNNnnnnn*n, NNNnnnnnn*, or NNNnnnnnnn*, wherin N* or n* represents abulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the −1, −2,and/or −3 position relative to the splice site of the splice sitesequence. For example, a target of an SMSM can be a pre-mRNA comprisinga splice site sequence of NNN*nnnnnn, NN*Nnnnnnn, or N*NNnnnnnn, wherinN* represents a bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with one or more bulged nucleotides at the +1, +2,+3, +4, +5, +6 and/or +7 position relative to the splice site of thesplice site sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NNNn*nnnnn, NNNnn*nnnn, NNNnnn*nnn,NNNnnnn*nn, NNNnnnnn*n, NNNnnnnnn*, or NNNnnnnnnn*, wherin n* representsa bulged nucleotide.

In some embodiments, a target of an SMSM is a pre-mRNA comprising asplice site sequence with a bulged nucleotide at the −1 positionrelative to the splice site of the splice site sequence and a bulgednucleotide at the −2 position relative to the splice site of the splicesite sequence. For example, a target of an SMSM can be a pre-mRNAcomprising a splice site sequence of NN*N*nnnnnn, wherin N* represents abulged nucleotide. In some embodiments, a target of an SMSM is apre-mRNA comprising a splice site sequence with a bulged nucleotide atthe −2 position relative to the splice site of the splice site sequenceand a bulged nucleotide at the −3 position relative to the splice siteof the splice site sequence. For example, a target of an SMSM can be apre-mRNA comprising a splice site sequence of N*N*Nnnnnnn, wherin N*represents a bulged nucleotide.

In some embodiments, an SMSM interacts with a bulged nucleotide of anRNA duplex comprising a splice site. In some embodiments, the RNA duplexcomprises pre-mRNA. In some embodiments, an SMSM binds to an RNA duplexand interacts with an unpaired bulged nucleobase of an RNA duplexcomprising a splice site. In some embodiments, a first portion of theSMSM interacts with the bulged nucleotide on a first RNA strand of theRNA duplex. In some embodiments, a second portion of the SMSM interactswith one or more nucleotides of a second RNA strand of the RNA duplex,wherein the first RNA strand is not the second RNA strand. In someembodiments, the SMSM forms one or more intermolecular interactions withthe duplex RNA, for example, an ionic interaction, a hydrogen bond, adipole-dipole interaction or a van der Waals interaction. In someembodiments, the SMSM forms one or more intermolecular interactions withthe bulged nucleotide, for example, an ionic interaction, a hydrogenbond, a dipole-dipole interaction or a van der Waals interaction.

In some embodiments, the duplex RNA comprises an alpha helix. In someembodiments, the bulged nucleotide is located on an external portion ofa helix of the duplex RNA. In some embodiments, the bulged nucleotide islocated within an internal portion of the helix of the duplex RNA.

In some embodiments, a rate of exchange of the bulged nucleotide fromwithin the interior of a helix of the duplex RNA to an exterior portionof the helix is reduced.

In some embodiments, the SMSM modulates a distance of the bulgednucleotide from a second nucleotide of the duplex RNA. In someembodiments, the SMSM reduces the distance of the bulged nucleotide froma second nucleotide of the duplex RNA. In some embodiments, the SMSMincreases the distance of the bulged nucleotide from a second nucleotideof the duplex RNA.

In some embodiments, the bulged nucleotide is located within theinterior of a helix of the duplex RNA of the complex. In someembodiments, the bulged nucleotide has modulated base stacking within anRNA strand of the RNA duplex. In some embodiments, the bulged nucleotidehas increased base stacking within an RNA strand of the RNA duplex. Insome embodiments, the bulged nucleotide has decreased base stackingwithin an RNA strand of the RNA duplex.

In some embodiments, the SMSM modulates splicing at the splice site ofthe RNA duplex. In some embodiments, the SMSM increases splicing at thesplice site of the RNA duplex. In some embodiments, the SMSM reducessplicing at the splice site of the RNA duplex. In some embodiments, theSMSM reduces a size of a bulge of the RNA duplex. In some embodiments,the SMSM removes a bulge of the RNA duplex. In some embodiments, theSMSM stabilizes a bulge of the RNA duplex.

In some embodiments, the unpaired bulged nucleotide is free to rotatearound a phosphate backbone of an RNA strand of the RNA duplex in theabsence of the SMSM. In some embodiments, the SMSM reduces a rate ofrotation of the unpaired bulged nucleotide. In some embodiments, theSMSM reduces a rate of rotation of the unpaired bulged nucleotide arounda phosphate backbone of an RNA strand of the RNA duplex.

In some embodiments, the SMSM is not an aptamer.

Also, provided herein is a method of modulating splicing comprisingcontacting a small molecule splicing modulator compound (SMSM) to acell; wherein the SMSM interacts with an unpaired bulged nucleotide ofan RNA duplex in the cell; wherein the duplex RNA comprises a splicesite; and wherein the SMSM modulates splicing of the RNA duplex.

Provided herein is a method for modulating the relative position of afirst nucleotide relative to a second nucleotide, wherein the firstnucleotide and the second nucleotide are within a duplex RNA, the methodcomprising contacting a small molecule splicing modulator compound(SMSM) to the duplex RNA, or a pharmaceutically acceptable salt thereof,wherein the first nucleotide is a bulged nucleotide of the RNA duplex;wherein the duplex RNA comprises a splice site.

In some embodiments, the duplex RNA comprises a helix.

In some embodiments, the bulged nucleotide is located on an externalportion of a helix of the duplex RNA prior to contacting the SMSM.

In some embodiments, SMSM forms one or more intermolecular interactionswith the duplex RNA.

In some embodiments, the SMSM forms one or more intermolecularinteractions with an unpaired bulged nucleotide. In some embodiments,the intermolecular interaction is selected from the group comprising anionic interaction, a hydrogen bond, a dipole-dipole interaction or a vander Waals interaction. In some embodiments, a rate of exchange of theunpaired bulged nucleotide from within the interior of a helix of theduplex RNA to an exterior portion of the helix is reduced. In someembodiments, a rate of rotation of the unpaired bulged nucleotide isreduced. In some embodiments, a rate of rotation of the unpaired bulgednucleotide around a phosphate backbone of an RNA strand of the RNAduplex is reduced. In some embodiments, a distance of the unpairedbulged nucleotide from a second nucleotide of the duplex RNA ismodulated after contacting the SMSM. In some embodiments, the distanceof the unpaired bulged nucleotide from a second nucleotide of the duplexRNA is reduced. In some embodiments, unpaired bulged nucleotide islocated within the interior of the helix of the duplex RNA. In someembodiments, a size of a bulge of the RNA duplex is reduced. In someembodiments, a bulge of the RNA duplex is removed or maintained.

In some embodiments, splicing at the splice site of the RNA duplex ispromoted. In some embodiments, base stacking of the unpaired bulgednucleotide within an RNA strand of the RNA duplex is increased aftercontacting the SMSM. In some embodiments, the distance of the unpairedbulged nucleotide from a second nucleotide of the duplex RNA isincreased or maintained. In some embodiments, a bulge of the RNA duplexis stabilized after contacting the SMSM. In some embodiments, theunpaired bulged nucleotide is located on an exterior portion of a helixof the duplex RNA. In some embodiments, a size of a bulge of the RNAduplex is increased. In some embodiments, splicing at the splice site ofthe RNA duplex is inhibited. In some embodiments, splicing is inhibitedat the splice site. In some embodiments, base stacking of the unpairedbulged nucleotide within an RNA strand of the RNA duplex is reducedafter contacting the SMSM.

Exemplary sites targeted by the SMSMs described herein include 5′ splicesites, 3′ splice sites, polypyrimidine tracts, branch sites, splicingenhancers and silencer elements. Mutations or aberrant secondary ortertiary RNA structures at hot spots can create mRNA sites or scaffoldsequences that can be targeted. For example, many exons are flanked bythe intronic dinucleotides GT and AG at the 5′ and 3′ splice sites,respectively. For example, mutations or aberrant secondary or tertiaryRNA structures at these sites can cause, e.g., exclusion of an adjacentexon or inclusion of an adjacent intron. Many factors influence thecomplex pre-mRNA splicing process, including several hundred differentproteins, at least five spliceosomal snRNAs, sequences on the mRNA,sequence length, enhancer and silencer elements, and strength ofsplicing signals.

Exemplary sites targeted by the SMSMs described herein include secondaryand sometimes tertiary structures of RNA. For example, exemplary sitestargeted by the SMSMs described herein include a stem loop, hairpin,branch point sequence (BPS), polypyrimidine tract (PPT), 5′ splice site(5′ss) and 3′ splice site (3′ss), duplex snRNA and splice sites andtrans acting protein binding to RNA. The target pre-mRNA can comprise adefective sequence, such as a sequence that produces a deficientprotein, such as a protein with altered function such as enzymeactivity, or expression, such as lack of expression. In someembodiments, the defective sequence impacts the structure of the RNA. Insome embodiments, the defect sequence impacts recognition by snRNP.

In addition to consensus splice site sequences, structural constraints,including those resulting from mutations, can affect cis-actingsequences such as exonic/intronic splicing enhancers (ESE/ISE) orsilencer elements (ESS/ISS).

In some embodiments, a mutation in native DNA and/or pre-mRNA, or anaberrant secondary or tertiary structure of RNA, creates a new splicesite sequence. For example, a mutation or aberrant RNA structure maycause native regions of the RNA that are normally dormant, or play norole as splicing elements, to become activated and serve as splice sitesor splice elements. Such splice sites and elements can be referred to as“cryptic”. For example, a native intron may become divided into twoaberrant introns, with a new exon situated there between. For example, amutation may create a new splice site between a native 5′ splice siteand a native branch point. For example, a mutation may activate acryptic branch point sequence between a native splice site and a nativebranch point. For example, a mutation may create a new splice sitebetween a native branch point and a native splice site and may furtheractivate a cryptic splice site and a cryptic branch point sequentiallyupstream from the aberrant mutated splice site.

In some embodiments, a mutation or misexpression of trans-actingproteins that regulate splicing activity may cause native regions of theRNA that are normally dormant, or play no role as splicing elements, tobecome activated and serve as splice sites or splice elements. Forexample, a mutation or misexpression of an SR protein may cause nativeregions of the RNA that are normally dormant, or play no role assplicing elements, to become activated and serve as splice sites orsplice elements.

In some embodiments, a mutation in native DNA and/or pre-mRNA inhibitssplicing at a splice site. For example, a mutation may result in a newsplice site upstream from (i.e., 5′ to) a native splice site sequenceand downstream from (i.e., 3′ to) a native branch point sequence. Thenative splice site sequence and the native branch point sequence mayserve as members of both the native set of splice site sequences and theaberrant set of splice site sequences.

In some embodiments, a native splice element (e.g., a branch point) isalso a member of the set of aberrant splice elements. For example, SMSMsprovided herein can block the native element and activate a crypticelement (e.g., a cryptic 5′ss, a cryptic 3′ss or a cryptic branchpoint), which may recruit remaining members of the native set of spliceelements to promote correct splicing over incorrect splicing. In someembodiments, an activated cryptic splice element is in an intron. Insome embodiments, an activated cryptic splice element is in an exon. Thecompounds and methods provided herein can be used to block or activate avariety of different splice elements, depending on the type of aberrantsplice element (e.g., mutated splice element or non-mutated spliceelement) and/or depending on regulation of a splice element (e.g.,regulation by upstream signaling pathways). For example, the compoundsand methods provided herein can block a mutated element, a non-mutatedelement, a cryptic element, or a native element; it may block a 5′splice site, a 3′ splice site, or a branch point.

In some embodiments, an alternate splicing event can be modulated byemploying the compounds provided herein. For example, a compoundprovided herein can be introduced into a cell in which a gene is presentthat encodes a pre-mRNA that comprises alternate splice sites. In someembodiments, in the absence of the compound, a first splicing eventoccurs to produce a gene product having a particular function. Forexample, in the presence of the compound provided herein, the firstsplicing event can be inhibited. In some embodiments, in the presence ofthe compound provided herein, the first splicing event can be inhibitedand a second or alternate splicing event occurs, resulting in expressionof the same gene to produce a gene product having a different function.

In some embodiments, a first inhibited splicing event (e.g., a splicingevent inhibited by a mutation, a mutation-induced bulge or anon-mutation induced bulge), is promoted or enhanced in the presence ofa compound provided herein. In some embodiments, the first inhibitedsplicing event (e.g., a splicing event inhibited by a mutation, amutation-induced bulge or a non-mutation induced bulge), is promoted orenhanced in the presence of a compound provided herein. For example, theinhibition of the first splicing event (e.g., a splicing event inhibitedby a mutation, a mutation-induced bulge or a non-mutation induced bulge)can be restored to a corresponding first splicing event that isuninhibited, in the presence of a compound provided herein; or theinhibition of the first splicing event can be decreased, in the presenceof a compound provided herein. In some embodiments, a second oralternate splicing event occurs, resulting in expression of the samegene to produce a gene product having a different function.

Target Polynucleotides

The compounds described herein can modulate splicing of gene products,such as those shown in Table 2A, Table 2B, Table 2C and Table 2D. Insome embodiments, the compounds described herein are use in thetreatment, prevention and/or delay of progression of diseases orconditions (e.g., cancer and neurodegenerative diseases). In someembodiments, the compounds described herein can modulate splicing andinduce a transcriptionally inactive variant or transcript of a geneproduct, such as those shown in Table 2A, Table 2B, Table 2C and Table2D. In some embodiments, the compounds described herein modulatesplicing and repress a transcriptionally active variant or transcript ofa gene product, such as those shown in Table 2A, Table 2B, Table 2C andTable 2D.

Modulation of splicing by the compounds described herein includes, butis not limited to, modulation of naturally occurring splicing, splicingof an RNA expressed in a diseased cell, splicing of cryptic splice sitesequences of an RNA or alternative splicing. Modulation of splicing bythe compounds described herein can restore or promote correct splicingor a desired splicing event. Modulation of splicing by the compoundsdescribed herein includes, but is not limited to, prevention of aberrantsplicing events, e.g., splicing events caused by mutations or aberrantsecondary or tertiary structures of RNA that are associated withconditions and diseases. In some embodiments, the compounds describedherein prevent or inhibit splicing at a splice site sequence. In someembodiments, the compounds described herein promote or increase splicingat a splice site sequence. In some embodiments, the compounds describedherein modulate splicing at a specific splice site sequence.

The compositions and methods described herein can be used to modulatesplicing of a target RNA, e.g., pre-mRNAs, encoded by genes. Examples ofgenes encoding a target RNA, e.g., a pre-mRNA, include, but are notlimited to the genes in Table 2A. Examples of genes encoding a targetRNA of the compositions and methods described herein, e.g., a pre-mRNA,include, but are not limited to ABCA4, ABCD1, ACADM, ACADSB, ADA,ADAMTS13, AGL, AGT, ALB, ALDH3A2, ALG6, ANGPTL3, APC, APOA1, APOB,APOC3, AR, ATM, ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M, BCL2-like 11(BIM), BMP2K, BRCA1, BRCA2, BTK, C3, CACNA1B, CACNA1C, CALCA, CAT, CD₃₃,CD₄₆, CDH1, CDH23, CFB, CFTR, CHM, CLCN1, COLiIA1, COL11A2, COLIA1,COL1A2, COL2A1, COL3A1, COL4A5, COL6A1, COL7A1, COL9A2, COLQ, CREBBP,CSTB, CUL4B, CYBB, CYP17, CYP19, CYP27A1, DES, DGAT2, DMD, DUX4, DYSF,EGFR, EMD, ETV4, F11, F13A1, F5, F7, F8, FAH, FANCA, FANCC, FANCG, FBN1,FECH, FGA, FGFR2, FGG, FIX, FLNA, FOXM1, FRAS1, GALC, GBA, GCGR, GH1,GHR, GHV, GLA, HADHA, HBA2, HBB, HEXA, HEXB, HLCS, HMBS, HMGCL, HNF1A,HPRTI, HPRT2, HSF4, HSPG2, HTT, IDHI, IDS, IKBKAP, IL7R^(A), INSR,ITGB2, ITGB3, ITGB4, JAG1, KLKB1, KRAS, KRT5, LI CAM, LAMA2, LAMA3,LDLR, LGALS3, LMNA, LPA, LPL, LRRK2, MADD, MAPT, MET, MLH1, MSH2, MSTIR,MTHFR, MUT, MVK, NFl, NF2, NR 1H4, OAT, OPAl, OTC, OXT, PAH, PBGD, PCCA,PDHl, PGKl, PHEX, PKD2, PKLR, PKM1, PKM2, PLEKHM1, PLKR, POMT2, PRDM1,PRKARIA, PROC, PSEN1, PTCHl, PTEN, PYGM, RP6KA3, RPGR, RSK2, SBCAD,SCN5A, SCNA, SERPINA1, SH2D1A, SLC12A3, SLC6A8, SMN2, SOD1, SPINK5,SPTAl, TMPRSS6, TP53, TRAPPC2, TSC1, TSC2, TSHB, TTN, TTR, UBE3A, UGT1A1and USH2A.

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2B. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to ABCD1, APOB, AR, AIM, BRCA1,C3, CFTR, COL1A1, COL3A1, COL6A1, COL7A1, CYP19, CYP27A1, DMD, F5, F7,FAH FBN1, EGA, GCK, GHV, HBA2, HBB, HMGCL, HPRT1, HXA, IDS, ITGB2,ITGB3, KRT5, LDLR, LMNA, LPL, MTHFR, NF1, NF2, PBGD, PGK1, PKD1, PTEN,RPGR. TP53, TSC2, UGT1A1 and YGM

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2C. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to genes encoding a target RNA,e.g., a pre-mRNA, with a splice site comprising a splice site sequenceof AGAguaag. Examples of genes encoding a target RNA of the compositionsand methods described herein, e.g., a pre-mRNA, include, but are notlimited to ABCA9, ABCB1, ABCB5, ACADL, ACSS2, ADAL, ADAM10, ADAM15,ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY8, AFP, AGL, AHCTF1, AKAP10,AKAP3, ALAS1, ALS2CL, AMBRA1, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2,AP4E1, APOB, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGEF18, ARHGEF2,ARPC3, ARS2. ASH1L, ASNSD1, ASPM, ATAD5, ATG4A, ATP11C, ATP6V1G3, BBOX1,BCS1L, BMPR2, BRCC3, BRSK2, C10orf137, C11orf70, C12orf51, C13orf1,C13orf15, C14orf118, C15orf29, C15orf42, C16orf33, C16orf38, C16orf48,C18orf8, C19orf42, C1orf107, C1orf114, C1orf130, C1orf149, C1orf27,C1orf11, C1orf94, C1K C20orf74, C21orf70, C3orf23, C4orf18, C5orf34,C8B, C8orf33, C9orf114, C9orf86, C9orf98, CA11, CAB39, CACNA2D1,CALCOCO2, CAMK1D, CAMKK1, CAPN9, CAPSL, CBX1, CBX3, CCDC102B, CCDC11,CCDC15, CCDC18, CCDC5, CCDC81, CD₄, CDC14A, CDC16, CDC2L5, CDC42BPB,CDCA8, CDH10, CDH11, CDH24, CDH8, CDH9, CDK5RAP2, CDK8, CELSR3, CENPI,CENTB2, CENTG2, CEP 110, CEP 170, CEP 192, CETP, CFH, CHAF1A, CHD9,CHIC2, CHN1, CLIC2, CLINT1, CLPB, CMIP, CNOT1, CNOT7, COG3, COL11A1,COL12A1, COL14A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1, COL25A1,COL29A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL9A1,COMTD1, COPA, COPB2, COPS7B, COPZ2, CPSF2, CPXM2, CR1, CREBBP, CRKRS,CSE1L, CT45-6, CUBN, CUL5, CXorf41, CYP3A4, CYP3A43, CYP3A5, DCC, DCTN3,DDA1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DHFR, DHRS7, DIP2A, DMD,DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7, DNTTIP2, DOCK11, DOCK4,DPP4, DSCC1, DYNC1H1, ECM2, EDEM3, EFCAB3, EFCAB4B, EIF3A, ELA1, ELA2A,EMCN, EMU, ENPP3, EPB41L5, EPHA3, EPHB1, EPHB3, EPS15, ERCC8, ERGIC3,ERMN, ERMP1, ERN1, ERN2, ETS2, EVC2, EXO1, EXOC4, F3, FAM13A1, FAM13B1,FAM13C1, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCM, FANK1,FAR2, FBXO15, FBXO18, FBXO38, FEZ2, FGFR10P, FGFR10P2, FGFR2, FGR,FLJ35848, FLJ36070, FLNA, FN1, FNBP1L, FOLH1, FRAS1, FUT9, FZD3, FZD6,GAB1, GALNT3, GART, GAS2L3, GCG, GJA1, GLT8D1, GNAS, GNB5, GOLGB1,GOLT1A, GOLT1B, GPATCH1, GPR160, GRAMD3, GRHPR, GRIM, GRIM, GRIM,GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GTPBP4, HDAC3, HDAC5, HDX,HEPACAM2, HERC1, HIPK3, HNRNPH1, HSPA9, HSPG2, HIT, ICA1, IF144L, IL1R2,IL5RA, IMMT, INPP5D, INTU, IP04, IP08, ISL2, IWS1, JAK1, JAK2, KATNAL2,KCNN2, KCNT2, KIAA0256, KIAA0586, KIAA1033, KIAA1219, KIAA1622, KIF15,KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KLF12,KLF3, KPNA5, KREMEN1, KRIT1, KRTCAP2, L1CAM, L3MBTL, L3MBTL2,LACE1HAMA2, LAMB1, LGMN, LHCGR, LHX6, LIMCH1, LIMK2, LMBRD1, LMBRD2,LMLN, LMO2, LOC390110, LPCAT2, LRP4, LRPPRC, LRRC19, LRRC42, LUM, LVRN,LYST, MADD, MAGI1, MAGT1, MALT1, MAP4K4, MAPK8IP3, MAPK9, MATN2, MCF2L2,MDGA2, MEGF10, MEGF11, MEMO1, MGAM, MGAT4A, MGC34774, MIB1, MIER2, MKL2,MLANA, MLL5, MLX, MME, MPI, MRAP2, MRPL39, MRPS28, MRPS35, MTDH, MTF2,MUC2, MYB, MYCBP2, MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3, NAG, NARG1,NARG2, NCOA1, NDFIP2, NEDD4, NEK1, NEK5, NFM, NFIX NFRKB, NKAP, NLRC3,NLRC5, NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1, NR4A3, NRXN1, NSMAF,NSMCE2, NT5C3, NUBP1, NUBPF, NUMA1, NUP160, NUP98, NUPL1, OBFC2B, OLIG2,OSBPL11, OSBPL8, OSGEPL1, PADI4, PAH, PAN2, PAPOLG, PARVB, PAWR, PCNX,PCOTH, PDCD4, PDE8B, PDIA3, PDK4, PDS5A, PDS5B, PHACTR4, PHKB, PHLDB2,PHTF1, PIAS1, PIGF, PIGN, PIGT, PIK3C2G, PIK3CG, PIK3R1, PIWIL3,PKHD1L1, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLXNC1, POLN,POLR3D, POMT2, POSTN, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2,PRAME, PRC1, PRIM1, PRIM2, PRKG1, PRMT7, PROCR, PROSC, PROX1, PRPF40B,PRPF4B, PRRG2, PSD3, PSMAL, PTK2, PTK2B, PTPN11, PTPN22, PTPN3, PTPN4,PTPRD, PTPRK, PTPRM, PUS 10, PVRL2, QRSL1, RAB11FIP2, RAB23, RB1CC1,RBM39, RBM45, REC8, RFC4, RHPN2, RLN3, RNF32, RNFT1, ROCK1, ROCK2, RP1,RP11-265F1, RP13-36C9, RPAP3, RPN1, RTEL1, RYR3, SAAL1, SAE1, SCN11A,SCN1A, SCN3A, SC01, SCYL3, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3,SENP6, SENP7, SETD3, SETD4, SGCE, SGOL2, SGPL1, SH3PXD2A, SH3PXD2B,SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SKAP1, SKIV2L2, SLC13A1, SLC28A3,SLC38A1, SLC38A4, SLC39A10, SLC4A2, SMARCA1, SMARCA5, SMC5, SNRK,SNRP70, SNX6, SPAG9, SPATA13, SPATA4, SPATS 1, SPECC1L, SPP2, SRP72,SSX3, SSX5, SSX9, STAG1, STAMBPL1, STARD6, STK17B, STX3, STXBP1, SUCLG2,SULF2, SUPT16H, SYCP1, SYTL5, TAF2, TBC1D3G, TBC1D8B, TBCEL, TBK1,TCEB3, TCF12, TCP11L2, TDRD3, TEAD1, TET2, TFRC, TG, THOC2, TIAL1,TIAM2, TIMM50, TLK2, TMEM156, TMEM27, IMF1, TNFRSF10A, TNFRSF10B,TNFRSF8, TNK2, INKS, TNKS2, TOM1L1, TOP2B, TP53INP1, TP63, TRAF3IP3,TRIM44, TRIM65, TRIML1, TRIML2, TRPM7, TTC17, TTLL5, TIN, TTPAL,UHRF1BP1, UNC45B, UNC5C, USP38, USP39, USP6, UTP15, UTP18, UTRN, UTX,UTY, UVRAG, UXT, VAPA, VPS29, VPS35, Mil A, VTI1B, VWA3B, WDFY2, WDR17,WDR26, WDR44, WDR67, WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS,ZBTB20, ZC3HA VI, ZC3HC1, ZNF114, ZNF365, ZNF37A, ZNF618 and ZWINT.

Examples of genes encoding a target RNA, e.g., a pre-mRNA, include, butare not limited to the genes in Table 2D. Examples of genes encoding atarget RNA of the compositions and methods described herein, e.g., apre-mRNA, include, but are not limited to genes encoding a target RNA,e.g., a pre-mRNA, with a splice site comprising a splice site sequenceof GGAgtaag. Examples of genes encoding a target RNA of the compositionsand methods described herein, e.g., a pre-mRNA, include, but are notlimited to ABCC9, ACTG2, ADAM22, ADAM32, ADAMTS12, ADCY3, ADRBK2, AFP,AKNA, APOH, ARHGAP26, ARHGAP8, ATG16L2, ATP13A5, B4GALNT3, BBS4, BRSK1,BTAF1, C11orf30. C11orf65, C14orf101, C15orf60, C1orf87, C2orf5,C4orf29, C6orf118, C9orf43, CACHD1, CACNA1G, CACNA1H, CAPN3, CARKD,CCDC131, CCDC146, CD1B, CDK6, CEL, CGN, CGNL1, CHU, CLEC16A, CLK1,CLPTM1, CMYA5, CNGA3, CNTN6, COL11A1, COL15A1, COL17A1, COL1A1, COL2A1,CRYZ CSTF3, CYFIP2, CYP24A1, CYP4F2, CYP4F3, DAZ2, DCBLD1, DCUN1D4,DDEF1, DDX1, DHRS9, DMTF1, DOCK10, DPP3, DPY19L2P2, DVL3, EFNA4, EFTUD2,EPHA4, EPHB2, ERBB4, ERCC1, FAM134A, FAM161A, FAM176B, FCGBP, FGD6,FKBP3, GAPDH GBGT1, GFM1, GPR158, GRIM, GSTCD, GSTO2, HCK, HLA-DPB1, HIAM. HLTF, HP1BP3, HPGD, HSF2BP, INTS3, IQGAP2, ITFG1, ITALG, ITGB1,ITIH1, ITPR2, JMJD1C, KALRN, KCNN2, KIAA0528, KIAA0564, KIAA1166.KIAA1409, KIAA1787, KIF3B, KLHL20, KLK12, LAMA1, LARP7, LENG1,LOC389634, LRWD1, LYN, MAP2K1, MCM6. MEGF10, MGAM, MGAT5, MGC16169,MKKS, MPDZ, MRPL11, MS4A13, MSMB, MTIF2, NDC80, NEB, NEK11, NFE2L2,NFKBIL2, NKAIN2, NLRC3, NLRC5, NLRP13, NLRP7, NLRP8, NT5C, NUDT5, NUP88,OBFC2A, OPN4, OPTN, PARD3, PBRM1, PCBP4, PDE10A, PDLIM5, PDXK, PDZRN3,PELI2, PGM2, PIP5K1A, PITRM1, PKIB, PMFBP1, POMT2, PRKCA, PRODH, PRUNE2,PTPRN2, PTPRT, RALBP1, RALGDS, RBL2, RFT1, RFTN1, PI 14. RMND5B, RNF11,RNGTT, RPS6KA6, RRM1, RRP1B, RTF1, RUFY1, SCN2A, SCN4A, SCN8A, SDK1,SEZ6, SFRS12, SH3BGRL2, SIVA1, SLC22A17, SLC25A14, SLC6A11, SLC6A13,SLC6A6, SMTN, SNCAIP, SNX6, STAT6, SUPT6H, SV2C, SYCP2, SYT6, TAF2,TBC1D26, TBC1D29, TBPL1, TECTB, TEK, TGM7, TGS1, TM4SF20, TM6SF1,TMEM194A, TMEM77, TOM1L2, TP53BP2, TP53I3, TRPM3, TRPM5, TSPAN7, TTLL9,TUSC3, TXNDC10, UCK1, USH2A, USP1, UTP20, VPS39, WDR16, ZC3H7A, ZFYVE1,7X4-469 and ZNF326.

The SMSM compounds and methods of their use described herein canmodulate splicing, such as aberrant splicing of polynucleotide encodedby a gene, e.g., an ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32,ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY3, ADCY8,ADRBK2, AFP, AGL, AGT, AHCTF1, AKAP10, AKAP3, AKNA, ALAS1, ALB, ALDH3A2,ALG6, ALS2CL, AMBRA1, ANGPTL3, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2,AP4E1, APC, APOA1, APOB, APOC3, APOH, A11. ARFGEF1, ARFGEF2, ARHGAP1,ARHGAP18, ARHGAP26, ARHGAP8, ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L,ASNSD1, ASPM, ATAD5, ATG16L2, ATG4A, ATM, ATP11C, ATP13A5, ATP6V1G3,ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M B4GALNT3, BBOX1, BBS4, BCL2-like 11(BIM), BCS1L, BMP2K, BMPR2, BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1,BTK, C10orf137, C11orf30, C11orf65, C11orf70, C12orf51, C13orf1,C13orf15, C14orf101, C14orf118, C15orf29, C15orf42, C15orf60, C16orf33,C16orf38, C16orf48, C18orf8, C19orf42, C1orf107, C1orf114, C1orf130,C1orf149, C1orf27, C1orf71, C1orf87, C1orf94, C1R, C20orf74, C21orf70,C2orf55, C3, C3orf23, C4orf18, C4orf29, C5orf34, C6orf118, C8B, C8orf33,C9orf114, C9orf43, C9orf86, C9orf98, CA11, CAB39, CACHD1, CACNA1B,CACNA1C, CACNA1G, CACNA1H, CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1,CAPN3, CAPN9, CAPSL, CARKD, CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131,CCDC146, CCDC15, CCDC18, CCDC5, CCDC81, CD1B, CD33, CD4, CD46, CDC14A,CDC16, CDC2L5, CDC42BPB, CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8,CDH9, CDK5RAP2, CDK6, CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP110,CEP170, CEP192, CETP, CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2,CHU, CHM, CHN1, CLCN1, CLEC16A, CLIC2, CLINT1, CLK1, CLPB, CLPTM1, CMIP,CMYA5, CNGA3, CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2, COL12A1,COL14A1, COL15A1, COL17A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1,COL25A1, COL29A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6,COL5A2, COL6A1, COL7A1, COL9A1, COL9A2, COLQ, COMTD1, COPA, COPB2,COPS7B, COPZ2, CPSF2, CPXM2, CR1, CREBBP, CRKRS, CRYZ, CSE1L, CSTB,CSTF3, CT45-6, CUBN, CUL4B, CUL5, CXorf41, CYBB, CYFIP2, CYP17, CYP19,CYP24A1, CYP27A1, CYP3A4, CYP3A43, CYP3A5, CYP4F2, CYP4F3, DAZ2, DCBLD1,DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2,DES, DGAT2, DHFR, DHRS7, DHRS9, DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1,DNAJA4, DNAJC13, DNAJC7, DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3, DPP4,DPY19L2P2, DSCC1, DUX4, DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3,EFCAB4B, EFNA4, EFTUD2, EGFR, EIF3A, ELA1, ELA2A, EMCN, EMD, EML5,ENPP3, EPB41L5, EPHA3, EPHA4, EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1,ERCC8, ERGIC3, ERMN, ERMP1, ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4,F11, F13A1, F3, F5, F7, F8, FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1,FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA,FANCC, FANCG, FANCM FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP,FECH FEZ2, FGA, FGD6, FGFR10P, FGFR10P2, FGFR2, FGG, FGR, FIX, FKBP3,FLJ35848, FLJ36070, FLNA, FN1, FNBP1L, FOLH1, FOXM1, FRAS1, FUT9, FZD3,FZD6, GAB1, GALC, GALNT3, GAPDH GART, GAS2L3, GBA, GBGT1, GCG, GCGR,GCK, GFM1, GH1, (HR. GHV GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGB1, GOLT1A,GOLT1B, GPATCH1, GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4,GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB,HCK HDAC3, HDAC5, HDX HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1,HLA-G, HLCS, HLTF, HMBS, HMGCL, HNF1A, HNRNPH1, HP IBP 3, HPGD, HPRT1,HPRT2, HSF2BP, HSF4, HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IF144L,IKBKAP, IL1R2, IL5RA, IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IPO4,IPO8, IQGAP2, ISL2, ITFG1, ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, ITIH1,ITPR2, IWS1, JAG1, JAK1, JAK2, JMJD1C, KALRN, KATNAL2, KCNN2, KCNT2,KIAA0256, KIAA0528, KIAA0564, KIAA0586, KIAA1033, KIAA1166. KIAA1219,KIAA1409, KIAA1622, KIAA1787, KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9,KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1,KPNA5, KRAS, KREMEN1, KRIT1, KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2,LACE1, LAMA1, LAMA2, LAMA3, LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN,LHCGR, LHX6, UMCH1, LIMK2, LMBRD1, IMBRD2, EMLN, LMNA, LMO2, LOC389634,LOC390110, LPA, LPCAT2, LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1,BUM LVRN, LYN, LYST, MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4,MAPK8IP3, MAPK9, MAPT, MATN2, MCF2L2, MCM6, MDGA2, MEGF10, MEGF11,MEMO1, MET, MGAM, MGAT4A, MGAT5, MGC16169, MGC34774, MIB1, MIER2, MKKS,MKL2, MLANA, MLH1, MLL5, MIX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39,MRPS28, MRPS35, MS4A13, MSH2, MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2,MUC2, MUT, MVK, MYB, MYCBP2, MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3,NAG, NARG1, NARG2, NCOA1, NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5,NF1, NF2, NFE2L2, NFIA, NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3,NLRC5, NLRP13, NLRP7, NLRP8, NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1,NR1H4, NR4A3, NRXN1, NSMAF, NSMCE2, NT5C, NT5C3, NUBP1, NUBPF NUDT5,NUMA1, NUP160, NUP88, NUP98, NUPL1, OAT OBFC2A, OBFC2B, OLIG2, OPA1,OPN4, OPEN, OSBPL11, OSBPL8, OSGEPL1, OTC, OXT, PADI4, PAH, PAN2,PAPOLG, PARD3, PARVB, PAWR, PBGD, PBRM1, PCBP4, PCCA, PCNX PCOTH, PDCD4,PDE10A, PDE8B, PDH1, PDIA3, PDK4, PDLIM5, PDS5A, PDS5B, PDXK, PDZRN3,PELI2, PGK1, PGM2, PHACTR4, PHEX, PHKB, PHLDB2, PHTF1, PIAS1, PIGF,PIGN, PYGM, PIK3C2G, PIK3CG, PIK3R1, PIP5K1A, PITRM1, PIWIL3, PKD1,PKD2, PKHD1L1, PKIB, PKLR, PKM1, PKM2, PLCB1, PLCB4, PLCG1, PLD1,PLEKHA5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2,POSTN, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1,PRDM1, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH,PROSC, PROX1, PRPF40B, PRPF4B, PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1,PTEN, PTK2, PTK2B, PTPN11, PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM,PTPRN2, PTPRT, PUS10, PVRL2, PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1,RALGDS, RB1CC1, RBL2, RBM39, RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2,RIF1, RLN3, RMND5B, RNF11, RNF32, RNFT1, RNGTT, ROCK1, ROCK2, RP1,RP11-265F1, RP13-36C9, RP6KA3, RPAP3, RPGR, RPN1, RPS6KA6, RRM1, RRP1B,RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1, SAE1, SBCAD, SOFIA. SCN1A, SCN2A,SCN3A, SCN4A, SCN5A, SCN8A, SCNA, SCO1, SCYL3, SDK1, SDK2, SEC24A,SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3, SETD4,SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A, SH3PXD2B,SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2, SLC12A3,SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1, SLC38A4, SLC39A10,SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1, SMARCA5, SMC5, SMN2,SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9, SPATA13, SPATA4, SPATS 1,SPECC1L, SPINK5, SPP2, SPTA1, SRP72, SSX3, SSX5, SSX9, STAG1, STAMBPL1,STARD6, STAT6, STK17B, STX3, STXBP1, SUCLG2, SULF2, SUPT16H, SUPT6H,SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2, TBC1D26, TBC1D29, TBC1D3G,TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12, TCP11L2, TDRD3, TEAD1, TECTB,TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2, TIAL1, TIAM2, TIMM50, TLK2,TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27, TMEM77, IMF1, TMPRSS6,TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, INKS, TNKS2, TOM1L1, TOM1L2, TOP2B,TP53, TP53BP2, TP53I3, TP53INP1, TP63, TRAF3IP3, TRAPPC2, TRIM44,TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1, TSC2, TSHB, TSPAN7,TTC17, TTLL5, TTLL9, TIN, TTPAL, TTR, TUSC3, TXNDC10, UBE3A, UCK1,UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1, USP38, USP39, USP6, UTP15,UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT, VAPA, VPS29, VPS35, VPS39, MilA. VTI1B, VWA3B, WDFY2, WDR16, WDR17, WDR26, WDR44, WDR67, WDTC1,WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS, YGM ZBTB20, ZC3H7A, ZC3HAV1,ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326, ZNF365, ZNF37A, ZNF618 or ZWINTgene.

For example, provided herein are splice modulating compounds thatmodulate splicing, such as aberrant splicing of ABCA4, ABCA9, ABCB1,ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, AD AMTS12, ADAMTS13, ADAMTS20, ADAMTS6,ADAMTS9, ADCY10, ADCY3, ADCY8, ADRBK2, AFP, AGL, AGT, AHCTF1, AKAP10,AKAP3, AKNA, ALAS1, ALB, ALDH3A2, ALG6, ALS2CL, AMBRA1, ANGPTL3, ANK3,ANTXR2, ANXA10, ANXA11, AP2A2, AP4E1, APC, APOA1, APOB, APOC3, APOH, AR,ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGAP26, ARHGAP8, ARHGEF18,ARHGEF2, ARPC3, ARS2, ASH1L, ASNSD1, ASPM, ATAD5, ATG16L2, ATG4A, ATM,ATP11C, ATP13A5, ATP6V1G3, ATP7A, ATP7B, ATR, ATXN2, ATXN3, B2M,B4GALNT3, BBOX1, BBS4, BCL2-like 11 (BIM), BCS1L, BMP2K, BMPR2, BRCA1,BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C10orf137, C11orf30, C11orf65,C11orf70, C12orf51, C13orf1, C13orf15, C14orf101, C14orf118, C15orf29,C15orf42, C15orf60, C16orf33, C16orf38, C16orf48, C18orf8, C19orf42,C1orf107, C1orf114, C1orf130, C1orf149, C1orf27, C1orf71, C1orf87,C1orf94, C1R, C20orf74, C21orf70, C2orf55, C3, C3orf23, C4orf18,C4orf29, C5orf34, C6orf118, C8B, C8orf33, C9orf114, C9orf43, C9orf86,C9orf98, CA11, CAB39, CACHD1, CACNA1B, CACNA1C, CACNA1G, CACNA1H,CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1, CAPN3, CAPN9, CAPSL, CARKD,CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131, CCDC146, CCDC15, CCDC18,CCDC15, CCDC81, CD₁B, CD₃₃, CD₄, CD₄₆, CDC14A, CDC16, CDCl₂L5, CDC42BPB,CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8, CDH9, CDK5RAP2, CDK6,CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP 110, CEP 170, CEP 192,CETP, CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2, CHL1, CHM, CHN1,CLCN1, CLEC16A, CLIC2, CLINT 1, CLK1, CLPB, CLPTM1, CMIP, CMYA5, CNGA3,CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2, COL12A1, COL14A1, COL15A1,COL17A1, COL19A1, COL1A1, COL1A2, COL22A1, COL24A1, COL25A1, COL29A1,COL2A1, COL3A1, COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL6A1, COL7A1,COL9A1, COL9A2, COLQ, COMTD1, COP A, COPB2, COPS7B, COPZ2, CPSF2, CPXM2,CR1, CREBBP, CRKRS, CRYZ, CSE1L, CSTB, CSTF3, CT45-6, CUBN, CUL4B, CUL5,CXorf41, CYBB, CYFIP2, CYP17, CYP19, CYP24A1, CYP27A1, CYP3A4, CYP3A43,CYP3A5, CYP4F2, CYP4F3, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1,DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9,DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7,DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3, DPP4, DPY19L2P2, DSCC1, DUX4,DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3, EFCAB4B, EFNA4, EFTUD2, EGFR,EIF3A, ELA1, ELA2A, EMCN, EMD, EML5, ENPP3, EPB41L5, EPHA3, EPHA4,EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1, ERCC8, ERGIC3, ERMN, ERMP1,ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4, FI 1, F13A1, F3, F5, F7, F8,FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1, FAM161A, FAM176B, FAM184A,FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1,FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, FEZ2, FGA, FGD6,FGFR1OP, FGFR10P2, FGFR2, FGG, FGR, FIX, FKBP3, FLJ35848, FLJ36070,FLNA, FN1, FNBP1L, FOLH1, FOXM1, FRAS1, FUT9, FZD3, FZD6, GAB1, GALC,GALNT3, GAPDH, GART, GAS2L3, GBA, GBGT1, GCG, GCGR, GCK, GFM1, GH1, GHR,GHV, GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGB1, GOLT1A, GOLT1B, GPATCH1,GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4,GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB, HCK, HDAC3, HDAC5,HDX, HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1, HLA-G, HLCS, HLTF,HMBS, HMGCL, HNF1A, HNRNPH1, HP1BP3, HPGD, HPRT1, HPRT2, HSF2BP, HSF4,HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IFI44L, IKBKAP, IL1R2, IL5RA,IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IPO4, IPO8, IQGAP2, ISL2, ITFG1,ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, ITIH1, ITPR2, IWS1, JAG1, JAK1, JAK2,JMJD1C, KALRN, KATNAL2, KCNN2, KCNT2, KIAA0256, KIAA0528, KIAA0564,KIAA0586, KIAA1033, KIAA1166, KIAA1219, KIAA1409, KIAA1622, KIAA1787,KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2,KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1, KPNA5, KRAS, KREMEN1, KRIT1,KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2, LACE1, LAMA1, LAMA2, LAM A3,LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN, LHCGR, LHX6, LIMCH1, LIMK2,LMBRD1, LMBRD2, LMLN, LMNA, LMO2, LOC389634, LOC390110, LPA, LPCAT2,LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1, LUM, LVRN, LYN, LYST,MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4, MAPK8IP3, MAPK9, MAPT, MATN2,MCF2L2, MCM6, MDGA2, MEGF10, MEGF11, MEMO1, MET, MGAM, MGAT4A, MGAT5,MGC16169, MGC34774, MIB1, MIER2, MKKS, MKL2, MLANA, MLH1, MLL5, MLX,MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2,MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2, MUC2, MUT, MVK, MYB, MYCBP2,MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3, NAG, NARG1, NARG2, NCOA1,NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5, NF1, NF2, NFE2L2, NFIA,NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3, NLRC5, NLRP13, NLRP7, NLRP8,NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1, NR1H4, NR4A3, NRXN1, NSMAF,NSMCE2, NT5C, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP160, NUP88, NUP98,NUPL1, OAT, OBFC2A, OBFC2B, OLIG2, OPA1, OPN4, OPTN, OSBPL11, OSBPL8,OSGEPL1, OTC, OXT, PADI4, PAH, PAN2, PAPOLG, PARD3, PARVB, PAWR, PBGD,PBRM1, PCBP4, PCCA, PCNX, PCOTH, PDCD4, PDE10A, PDE8B, PDH1, PDIA3,PDK4, PDLIM5, PDS5A, PDS5B, PDXK, PDZRN3, PELI2, PGK1, PGM2, PHACTR4,PHEX, PHKB, PHLDB2, PHTF1, PIAS1, PIGF, PIGN, PIGT, PIK3C2G, PIK3CG,PIK3R1, PIP5K1A, PITRM1, PIWIL3, PKD1, PKD2, PKHD1L1, PKIB, PKLR, PKM1,PKM2, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLEKHM1, PLKR,PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, PPFIA2, PPP1R12A, PPP3CB,PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PRIM1, PRIM2, PRKAR1A,PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH, PROSC, PROX1, PRPF40B, PRPF4B,PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1, PTEN, PTK2, PTK2B, PTPN11,PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM, PTPRN2, PTPRT, PUS10, PVRL2,PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1, RALGDS, RB1CC1, RBL2, RBM39,RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2, RIF1, RLN3, RMND5B, RNF11, RNF32,RNFT1, RNGTT, ROCK1, ROCK2, RP1, RP11-265F1, RP13-36C9, RP6KA3, RPAP3,RPGR, RPN1, RPS6KA6, RRM1, RRP1B, RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1,SAE1, SBCAD, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA,SCO1, SCYL3, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6,SENP7, SERPINA1, SETD3, SETD4, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A,SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1,SKAP1, SKIV2L2, SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1,SLC38A4, SLC39A10, SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1,SMARCA5, SMC5, SMN2, SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9,SPATA13, SPATA4, SPATS1, SPECC1L, SPINK5, SPP2, SPTA1, SRP72, SSX3,SSX5, SSX9, STAG1, STAMBPL1, STARD6, STAT6, STK17B, STX3, STXBP1,SUCLG2, SULF2, SUPT16H, SUPT6H, SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2,TBC1D26, TBC1D29, TBC1D3G, TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12,TCP11L2, TDRD3, TEAD1, TECTB, TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2,TIAL1, TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27,TMEM77, TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2,TOM1L1, TOM1L2, TOP2B, TP53, TP53BP2, TP53I3, TP53INP1, TP63, TRAF3IP3,TRAPPC2, TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1,TSC2, TSHB, TSPAN7, TTC17, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3,TXNDC10, UBE3A, UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1,USP38, USP39, USP6, UTP15, UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT,VAPA, VPS29, VPS35, VPS39, VTI1A, VTI1B, VWA3B, WDFY2, WDR16, WDR17,WDR26, WDR44, WDR67, WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS,YGM, ZBTB20, ZC3H7A, ZC3HAV1, ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326,ZNF365, ZNF37A, ZNF618 or a ZWINT mRNA, such as pre-mRNA.

In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ABCA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCA9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCB5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCC9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ABCD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACADSB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACSS2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ACTG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ADA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ADAL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM 10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM22. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAM32. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS12. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS13. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS20. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADAMTS9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADCY10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ADCY3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ADCY8. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofADRBK2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of AFP. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AGL. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of AGT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AHCTF1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AKAP10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AKAP3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of AKNA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of ALAS1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ALB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ALDH3A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ALG6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ALS2CL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of AMBRA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ANGPTL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ANK3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ANTXR2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofANXA10. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ANXA11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AP2A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of AP4E1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of APC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of APOA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of APOB. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of APOC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofAPOH. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of AR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARFGEF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARFGEF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP26. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGAP8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGEF18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARHGEF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARPC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ARS2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ASH1L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ASNSD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ASPM. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ATAD5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofATG16L2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of ATG4A. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ATM. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ATP1IC. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP13A5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP6V1G3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ATP7A. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ATP7B. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofATR. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ATXN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ATXN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of B2M. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of B4GALNT3. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of BBOX1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of BBS4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofBCL2-like 11 (BIM). In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofBCS1L. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of BMP2K. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BMPR2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRCC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRSK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BRSK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BTAF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of BTK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of C10orf137. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf30. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf65. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf70. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C12orf51. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C13orf1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C13orf15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C14orf101. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C14orf118. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf29. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C15orf60. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C16orf33. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C16orf38. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C16orf48. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C18orf8. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C19orf42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf107. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf114. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf130. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf149. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf27. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf71. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf87. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C11orf94. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C1R. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of C20orf74. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of C21orf70. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of C2orf55. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA of C3.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of C3orf23. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C4orf18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C4orf29. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C5orf34. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C6orf118. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of C8B. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of C8orf33. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf114. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf43. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf86. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of C9orf98. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CA11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CAB39. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCACHD1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CACNA1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1G. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA1H. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CACNA2D1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CALCA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CALCOCO2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAMK1D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAMKK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPN9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAPSL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CARKD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CAT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CBX1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CBX3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CCDC102B. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of CCDC11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCCDC131. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of CCDC146. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC18. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CCDC181. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CD₁B. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CD₃₃. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CD₄. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CD₄₆. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofCDC14A. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CDC16. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDCl₂L5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDC42BPB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDCA8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CDH10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CDH11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CDH23. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCDH24. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CDH8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CDH9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CDK5RAP2. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CDK6. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CDK8. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CEL.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CELSR3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENPI. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENTB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CENTG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP110. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP170. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CEP192. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CETP. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CFB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CFH. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CFTR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CGN.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CGNL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CHAF1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CHD9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CHIC2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CHL1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CHM. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CHN1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CLCN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLEC16A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLIC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLINT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CLK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CLPB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CLPTM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CMIP. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CMYA5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCNGA3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CNOT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CNOT7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CNTN6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COG3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of COL11AL. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL11A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL12A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL14A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL15A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL17A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL19A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL1AL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL 1A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL22A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL24A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL25A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL29A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL2A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL3A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL4A6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL5A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL6A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL7A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL9A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COL9A2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of COLQ. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of COMTD1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCOPA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of COPB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COPS7B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of COPZ2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CPSF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CPXM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CR1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CREBBP. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CRKRS. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CRYZ. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of CSE1L.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CSTB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CSTF3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CT45-6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CUBN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of CUL4B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of CUL5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of CXorf41. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofCYBB. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of CYFIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP19. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP24A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP27A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A43. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP3A5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP4F2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of CYP4F3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DAZ2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DCBLD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DCC. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DCTN3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDCUN1D4. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of DDA1. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DDEF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DDX1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DDX24. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DDX4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DENND2D. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDEPDC2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of DES. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DGAT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DHFR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DHRS7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DHRS9. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DIP2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofDMD. For example, the SMSM compounds and methods of their use describedherein can modulate splicing of exon 51a pre-mRNA of DMD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DMTF1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAH3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAH8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAI1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJC13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNAJC7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DNTTIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DOCK4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DPP3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of DPP4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DPY19L2P2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of DSCC1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of DUX4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of DVL3.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of DYNC1H1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of DYSF. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ECM2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EDEM3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of EFCAB3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEFCAB4B. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of EFNA4. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EFTUD2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EGFR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of EIF3A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ELA1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ELA2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEMCN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of EMD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EML5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ENPP3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EPB41L5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EPHA3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of EPHA4. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofEPHB1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of EPHB2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EPHB3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EPS15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERBB4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERCC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERCC8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERGIC3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ERMN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ERMP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ERNI. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ERN2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of ETS2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ETV4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of EVC2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of EXO1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of EXOC4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of F1l1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of F3AL.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of F3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of F5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of F7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of F8. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FAH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofFAM134A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of FAM13A1. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM13B1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM13C1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM161A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM176B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM184A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM19A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM20A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM23B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAM65C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCC. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCG. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANCM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FANK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FAR2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FBN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO18. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FBXO38. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FCGBP. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FECH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of FEZ2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FGA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FGD6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FGFR1OP. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FGFR1OP2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FGFR2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FGG. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of FGR.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FIX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FKBP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLJ35848. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLJ36070. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FLNA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FNBP1L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of FOLH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of FOXM1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofFRAS1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of FUT9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of FZD3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of FZD6. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GAB1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GALC. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofGALNT3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GAPDH. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GART. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GAS2L3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GBA. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GBGT1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofGCG. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GCGR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GCK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GFM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GHR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of GHV.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GJA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GLA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GLT8D1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GNAS. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GNB5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofGOLGB1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GOLT1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GOLT1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPATCH1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPR158. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GPR160. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRAMD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRHPR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIA4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRIN2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GRM3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of GRM4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of GRN. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of GSDMB. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofGSTCD. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of GSTO2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of GTPBP4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HADHA. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HBA2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HBB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HCK. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HDAC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHDAC5. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HDX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HEPACAM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HERC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HEXA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HEXB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HIPK3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HLA-DPB1. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of HLA-G. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHLCS. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HLTF. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HMBS. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HMGCL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HNF1A. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HNRNPH1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofHP1BP3. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of HPGD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HPRT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HPRT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HSF2BP. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of HSF4. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of HSPA9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of HSPG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of HTT. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of HXA.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ICAL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of IDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of IDS. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IFI44L. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IKBKAP. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of IL1R2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of IL5RA. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofIL7RA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of IMMT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of INPP5D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of INSR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of INTS3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of INTU. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of IPO4. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of IPO8.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of IQGAP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ISL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of ITFG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of ITGAL. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of ITGB1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofITGB2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ITGB3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ITGB4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of IT1H1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ITPR2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of IWS1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of JAGI. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of JAK1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of JAK2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofJMJD1C. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of KALRN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KATNAL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KCNN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KCNT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0256. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0528. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0564. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA0586. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1033. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1166. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1219. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1409. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1622. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIAA1787. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF15. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF16B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF3B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF5A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF5B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KIF9. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of KIN. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR2DL5B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR3DL2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KIR3DL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KLF12. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of KLF3. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofKLHL20. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of KLK12. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KLKB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KPNA5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of KRAS. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of KREMEN1. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of KRIT1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of KRT5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofKRTCAP2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of L1CAM. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of L3MBTL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of L3MBTL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LACE1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMA3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LAMB1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LARP7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LDLR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LENG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LGALS3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LGMN. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LHCGR. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofLHX6. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LIMCH1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LIMK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMBRD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMBRD2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LMLN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LMNA. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LMO2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LOC389634. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of LOC390110. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of LPA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofLPCAT2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LPL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LRP4. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LRPPRC. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRC19. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRC42. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of LRRK2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of LRWD1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofLUM. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of LVRN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of LYN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of LYST. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MADD. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MAGI1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMAGT1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MALT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAP2K1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAP4K4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPK8IP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPK9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MAPT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MATN2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MCF2L2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MCM6. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MDGA2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMEGF10. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MEGF11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MEMO1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MET. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MGAM. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MGAT4A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MGAT5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MGC16169. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of MGC34774. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of MIBl. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MIER2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MKKS. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MKL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MLANA. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MLH1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MLL5. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MLX.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MME. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MPDZ. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MPI. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MRAP2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MRPL11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofMRPL39. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MRPS28. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MRPS35. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MS4A13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MSH2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MSMB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MST1R. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MTDH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of MTF2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MTHFR. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MTIF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MUC2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of MUT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of MVK. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of MYB. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofMYCBP2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of MYH2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO19. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO3A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYO9B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYOM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of MYOM3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NAG. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NARG1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NARG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NCOA1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNDC80. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NDFIP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NEB. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NEDD4. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NEK1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NEK11. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNEK5. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NFl. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NF2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NFE2L2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NFIA. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NFIX. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofNFKBIL2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of NFRKB. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NKAIN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NKAP. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NLRC3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NLRC5. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NLRP13. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNLRP7. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NLRP8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NME7. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NOL10. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NOSi. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NOS2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNOTCH1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NPM1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NR1H4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NR4A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NRXN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NSMAF. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NSMCE2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NT5C. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of NT5C3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NUBP 1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of NUBPL. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of NUDT5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofNUMAL. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of NUP160. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUP88. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUP98. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of NUPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OAT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of OBFC2A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of OBFC2B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of OLIG2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of OPAL. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of OPN4.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of OPTN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSBPL11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSBPL8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OSGEPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of OTC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of OXT. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PADI4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PAH. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of PAN2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PAPOLG. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PARD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PARVB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PAWR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PBGD. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PBRM1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PCBP4. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPCCA. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PCNX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PCOTH. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDCD4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDE10A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDE8B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDH1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PDIA3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PDK4. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PDLIM5. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPDS5A. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PDS5B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PDXK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PDZRN3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PELI2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PGK1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of PGM2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PHACTR4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PHEX. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PHKB. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PHLDB2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PHTF1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PIAS1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPIGF. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PIGN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PIGT. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PIK3C2G. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIK3CG. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIK³R¹. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIP5K1A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PITRM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PIWIL3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PKD1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PKD2. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofPKHDIL1. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of PKIB. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PKLR. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PKM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PKM2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PLCB1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPLCB4. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PLCG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PLD1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PLEKHA5. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLEKHA7. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLEKHM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PLKR. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PLXNC1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPMFBP1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of POLN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POLR3D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POMT2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of POSTN. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPFIA2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP1R12A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP3CB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4R1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PPP4R2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRAME. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRC1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PRDM1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PRIM1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PRIM2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPRKAR1A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of PRKCA. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRKG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRMT7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PROC. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PROCR. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PRODH. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PROSC. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPROX1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PRPF40B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRPF4B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRRG2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PRUNE2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PSD3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of PSEN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of PSMAL. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of PTCH1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofPTEN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of PTK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTK2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN22. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPN4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRD. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRK. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRM. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PTPRT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PUS10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PVRL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of PYGM. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of QRSL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RAB11FIP2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RAB23. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RALBP1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRALGDS. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RB1CC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RBL2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RBM39. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RBM45. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of REC8. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of RFC4.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RFT1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RFTN1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RHPN2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RIF1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RLN3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RMND5B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RNF11. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RNF32. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRNFT1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RNGTT. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ROCK1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ROCK2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RP 1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RP11-265F1. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RP13-36C9. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RP6KA3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RPAP3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RPGR. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of RPN1.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RPS6KA6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RRM1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of RRP1B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of RSK2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of RTEL1. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofRTF1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of RUFY1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of RYR3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SAAL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SAE1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SBCAD. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSCN11 A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of SCN1A. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN2A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN3A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN4A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN5A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCN8A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SCNA. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SCO1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SCYL3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SDK1. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of SDK2.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SEC24A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEC24D. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEC31A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEL1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SENP7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SERPINAL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SETD3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SETD4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SEZ6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SFRS12. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SGCE. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SGOL2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSGPL 1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SH2D1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3BGRL2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3PXD2A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3PXD2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3RF2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SH3TC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIPA1L2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIPA1L3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SIVA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SKAP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SKIV2L2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC12A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC13A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC22A17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC25A14. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC28A3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC38A1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC38A4. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC39A10. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC4A2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A11. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A13. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SLC6A8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMARCA1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMARCA5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SMC5. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SMN2. For example, the SMSM compoundsand methods of their use described herein can modulate splicing of exon7 of a pre-mRNA of SMN2. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of SMTN. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA ofSNCAIP. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SNRK. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SNRP70. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SNX6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SOD1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SPAG9. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SPATA13. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSPATA4. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SPATS1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPECC1L. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPINK5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SPP2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SPTA1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SRP72. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SSX3. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of SSX5.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SSX9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STAG1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STAMBPL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STARD6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STAT6. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STK17B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of STX3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of STXBP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SUCLG2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of SULF2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of SUPT16H. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofSUPT6H. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of SV2C. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYCP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYCP2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of SYT6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of SYTL5. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TAF2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TBC1D26. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTBC1D29. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TBC1D3G. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBC1D8B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBCEL. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TBK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TBPL1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TCEB3. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TCF12. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTCP11L2. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TDRD3. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TEAD1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TECTB. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TEK. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TET2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TFRC. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TG. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of TGM7.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TGS1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of THOC2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIAL1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIAM2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TIMM50. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TLK2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TM4SF20. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TM6SF1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM156. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM194A. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM27. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMEM77. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TMF1. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TMPRSS6. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTNFRSF10A. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of TNFRSF10B.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TNFRSF8. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TNK2. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TNKS. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TNKS2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TOM1LL. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTOM1L2. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TOP2B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TP53. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TP53BP2. In some embodiments, theSMSM compounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP53I3. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP53INP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TP63. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TRAF3IP3. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of TRAPPC2. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTRIM44. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TRIM65. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRIML1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRIML2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM3. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TRPM7. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TSC1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TSC2. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TSHB. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TSPAN7. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTTC17. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of TTLL5. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TTLL9. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of TTN. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of TTPAL. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of TTR. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of TUSC3. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofTXNDC10. In some embodiments, the SMSM compounds and methods of theiruse described herein can modulate splicing of a pre-mRNA of UBE3A. Insome embodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of UCK1. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UGT1A1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UHRF1BP1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UNC45B. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UNC5C. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of USH2A. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofUSP1. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of USP38. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of USP39. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of USP6. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UTP15. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UTP18. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of UTP20. In some embodiments, the SMSM compounds and methodsof their use described herein can modulate splicing of a pre-mRNA ofUTRN. In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of UTX. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of UTY. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of UVRAG. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of UXT. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of VAPA. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of VPS29.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of VPS35. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VPS39. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VTI1A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VTI1B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of VWA3B. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDFY2. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR16. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR17. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR26. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR44. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDR67. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WDTC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WRNIP1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of WWC3. In some embodiments,the SMSM compounds and methods of their use described herein canmodulate splicing of a pre-mRNA of XRN1. In some embodiments, the SMSMcompounds and methods of their use described herein can modulatesplicing of a pre-mRNA of XRN2. In some embodiments, the SMSM compoundsand methods of their use described herein can modulate splicing of apre-mRNA of XX-FW88277. In some embodiments, the SMSM compounds andmethods of their use described herein can modulate splicing of apre-mRNA of YARS. In some embodiments, the SMSM compounds and methods oftheir use described herein can modulate splicing of a pre-mRNA of YGM.In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing of a pre-mRNA of ZBTB20. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3H7A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3HAV1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZC3HC1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZFYVE1. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF114. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF169. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF326. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF365. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF37A. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZNF618. In someembodiments, the SMSM compounds and methods of their use describedherein can modulate splicing of a pre-mRNA of ZWINT.

In some embodiments, the SMSM compounds and methods of their usedescribed herein can modulate splicing, such as alternative splicing ofa polynucleotide encoded by MAPT gene. In some embodiments, alternativesplicing of the MAPT pre-mRNA may lead to the expression of 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 isoforms of the tau protein. In some embodiments,alternative splicing of the MAPT pre-mRNA may lead to the expression of6 isoforms of the tau protein. In some embodiments, the 6 isoforms oftau include 3 four-repeat (4R) isoforms and 3 three-repeat (3R) isoformsof the tau protein. In the 3R tau isoforms exon 10 is excluded from thesplice variants. For example, a 3R tau isoform in which exon 10 isexcluded may include exon 2 and/or exon 3. In the 4R tau isoforms exon10 is included in the splice variants. For example, a 4R tau isoform inwhich exon 10 is included may include exon 2 and/or exon 3. Theinclusion or exclusion of exon 10 may depend on alternative splicingevents in a stem loop occurring at the exon 10 intron 10 junction. Insome embodiments, a mutation occurring at the 5′ss results in inclusionof exon 10 in an mRNA encoding the tau protein. In some embodiments, amutation in an ISS region of the stem loop results in exclusion of exon10 from the mRNA encoding the tau protein. In some embodiments, amutation at the 5′ss destabilizes the stem loop, thereby decreasing exon10 inclusion in the mRNA of tau. In some embodiments, a mutation at the5′ss inhibits binding of a spliceosome component to the pre-mRNA,thereby decreasing exon 10 inclusion in the mRNA of tau. In someembodiments, a mutation at the ISS region of the stem loop inhibitsbinding of a spliceosome component to the pre-mRNA, thereby increasingexon 10 inclusion in the mRNA of tau.

The ratio of 3R to 4R tau isoforms may contribute to a number ofconditions or diseases. In some embodiments, a subject without acondition or disease has a 3R to 4R ratio of 1:1. In some embodiments, asubject with a condition or disease described herein has a 3R to 4Rratio of about 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4,1:4.5 or 1:5. In some embodiments, a subject with a condition or diseasedescribed herein has a 3R to 4R ratio from about 1:1 to about 1:1.1,about 1:1 to about 1:1.2, about 1:1 to about 1:1.3, about 1:1 to about1:1.4, about 1:1 to about 1:1.5, about 1:1 to about 1:1.6, about 1:1 toabout 1:1.8, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1to about 1:3.5, about 1:1 to about 1:4, about 1:1 to about 1:4.5, about1:1 to about 1:5, 1:2 to about 1:3, about 1:2 to about 1:4, about 1:2 toabout 1:5, about 1:3 to about 1:4, about 1:3 to about 1:5, or about 1:4to about 1:5. In some embodiments, a subject with a condition or diseasedescribed herein has a 4R to 3R ratio of about 1:1.2, 1:1.4, 1:1.6,1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5. In some embodiments, asubject with a condition or disease described herein has a 4R to 3Rratio from about 1:1 to about 1:1.1, about 1:1 to about 1:1.2, about 1:1to about 1:1.3, about 1:1 to about 1:1.4, about 1:1 to about 1:1.5,about 1:1 to about 1:1.6, about 1:1 to about 1:1.8, about 1:1 to about1:2, about 1:1 to about 1:3, about 1:1 to about 1:3.5, about 1:1 toabout 1:4, about 1:1 to about 1:4.5, about 1:1 to about 1:5, 1:2 toabout 1:3, about 1:2 to about 1:4, about 1:2 to about 1:5, about 1:3 toabout 1:4, about 1:3 to about 1:5, or about 1:4 to about 1:5.

In some aspects, the SMSM compounds are used to modulate alternativesplicing of tau pre-mRNA. In some embodiments, the SMSM compound bindsto the stem loop of exon 10 of the tau pre-mRNA, reducing bindingaffinity of a spliceosome component to the 5′ss, thereby increasingexclusion of exon 10 in the mRNA of tau and increasing the ratio of3R:4R tau isoforms. In some embodiments, the SMSM compound binds to thestem loop of exon 10 of the tau pre-mRNA, increasing binding affinity ofa spliceosome component to the 5′ss, thereby increasing inclusion ofexon 10 in the mRNA of tau and decreasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, reducing binding affinity of aspliceosome component to the ISS region, thereby increasing inclusion ofexon 10 in the mRNA of tau and decreasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, increasing binding affinity of aspliceosome component to the ISS region, thereby reducing inclusion ofexon 10 in the mRNA of tau and increasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound restores the ratio of3R:4R to 1:1. In some embodiments, the SMSM compound alters the ratiofrom 3R>4R to 4R>3R. In some embodiments, the SMSM compound alters theratio from 3R<4R to 4R<3R. In some embodiments, the SMSM compound bindsto the stem loop of exon 10 of the tau pre-mRNA, increasing thethermodynamic stability of the stem loop, thereby reducing inclusion ofexon 10 in the mRNA of tau and increasing the ratio of 3R:4R tauisoforms. In some embodiments, the SMSM compound binds to the stem loopof exon 10 of the tau pre-mRNA, decreasing the thermodynamic stabilityof the stem loop, thereby increasing inclusion of exon 10 in the mRNA oftau and decreasing the ratio of 3R:4R tau isoforms.

Mutations and/or aberrant secondary or tertiary RNA structures incis-acting elements of splicing can alter splicing patterns. Mutationsand/or aberrant secondary or tertiary RNA structures can be found incore consensus sequences, including 5′ss, 3′ss, and BP regions, or otherregulatory elements, including ESEs, ESSs, ISEs, and ISSs. Mutations incis-acting elements can result in multiple diseases. Exemplary diseasesare described below. The present disclosure provides splice modulatingcompounds and methods that target pre-mRNA containing one or moremutations and/or aberrant secondary or tertiary RNA structures incis-acting elements. In some embodiments, the present disclosureprovides methods and small molecule binding agents that target pre-mRNAcontaining one or more mutations and/or aberrant secondary or tertiaryRNA structures in splice sites or BP regions. In some embodiments, thepresent disclosure provides methods and small molecule binding agentsthat target pre-mRNA containing one or more mutations and/or aberrantsecondary or tertiary RNA structures in other regulatory elements, forexample, ESEs, ESSs, ISEs, and ISSs.

In some embodiments, splicing at a splice site sequence of apolynucleotide of primary cells is modulated. In some embodiments,splicing at a splice site sequence of a polynucleotide of cells of atumor is modulated. In some embodiments, the SMSM modulates splicing ata cryptic splice site sequence. In some embodiments, an SMSM modulatessplicing of splice site of a polynucleotide. In some embodiments,wherein the polynucleotide is transcribed from the gene. In someembodiments, SMSM modulates exon inclusion in the polynucleotide andsplicing of the splice site sequence. In some embodiments, the SMSMmodulates pseudoexons inclusion in the polynucleotide and splicing ofthe splice site sequence. In some embodiments, the SMSM modulatessplicing at a cryptic splice site sequence of a polynucleotide.

In some embodiments, an SMSM modulates splicing by preventing,inhibiting or reducing splicing of the polynucleotide. In someembodiments, an SMSM modulates splicing by preventing, inhibiting orreducing splicing at the splice site sequence. In some embodiments, anSMSM decreases affinity of a splicing complex component to thepolynucleotide. In some embodiments, an SMSM decreases affinity of asplicing complex component to the polynucleotide at the splice sitesequence, upstream of the splice site sequence or downstream of thesplice site sequence. In some embodiments, an SMSM inhibits or reduces arate of catalysis of splicing of the polynucleotide. In someembodiments, an SMSM inhibits or reduces a rate of catalysis of splicingof the polynucleotide at the splice site sequence. In some embodiments,an SMSM increases steric hindrance between a splicing complex componentand the polynucleotide. In some embodiments, an SMSM increases sterichindrance between a splicing complex component and the polynucleotide atthe splice site sequence, upstream of the splice site sequence ordownstream of the splice site sequence. In some embodiments, an SMSMincreases steric hindrance between a first splicing complex componentand a second splicing complex component. In some embodiments, an SMSMprevents, inhibits, disrupts or reduces binding of a first splicingcomplex component and a second splicing complex component.

In some embodiments, an SMSM decreases affinity of a first splicingcomplex component to a second splicing complex component. In someembodiments, an SMSM prevents, inhibits, disrupts or reduces binding ofa splicing complex component to the polynucleotide. In some embodiments,an SMSM prevents, inhibits, disrupts or reduces binding of a splicingcomplex component to the polynucleotide at the splice site sequence,upstream of the splice site sequence or downstream of the splice sitesequence.

In some embodiments, an SMSM modulates splicing by promoting orincreasing splicing of the polynucleotide. In some embodiments, an SMSMmodulates splicing by promoting or increasing splicing the splice sitesequence. In some embodiments, an SMSM increases affinity of a splicingcomplex component to the polynucleotide. In some embodiments, an SMSMincreases affinity of a splicing complex component to the polynucleotideat the splice site sequence, upstream of the splice site sequence ordownstream of the splice site sequence. In some embodiments, an SMSMincreases a rate of catalysis of splicing of the polynucleotide. In someembodiments, an SMSM increases a rate of catalysis of splicing of thepolynucleotide at the splice site sequence. In some embodiments, an SMSMdecreases or reduces steric hindrance between a splicing complexcomponent and the polynucleotide. In some embodiments, an SMSM decreasessteric hindrance between a splicing complex component and thepolynucleotide at the splice site sequence, 1-1000 nucleobases basesupstream of the splice site sequence or 1-1000 nucleobases downstream ofthe splice site sequence. In some embodiments, an SMSM decreases orreduces steric hindrance between a first splicing complex component anda second splicing complex component. In some embodiments, an SMSMpromotes or increases binding of a first splicing complex component anda second splicing complex component. In some embodiments, an SMSMincreases affinity of a first splicing complex component to a secondsplicing complex component. In some embodiments, an SMSM promotes orincreases binding of a splicing complex component to the polynucleotide.In some embodiments, an SMSM promotes or increases binding of a splicingcomplex component to the polynucleotide at the splice site sequence,1-1000 nucleobases upstream of the splice site sequence or 1-1000nucleobases downstream of the splice site sequence. In some embodiments,an SMSM binds to a splicing complex component, the polynucleotide, or acombination thereof. In some embodiments, an SMSM binds to thepolynucleotide at the splice site sequence, 1-1000 nucleobases upstreamof the splice site sequence or 1-1000 nucleobases downstream of thesplice site sequence. In some embodiments, an SMSM structurallymodulates a splicing complex component, the polynucleotide, or both. Insome embodiments, an SMSM promotes or increases steric hindrance, stericshielding, steric attraction, chain crossing, steric repulsions, stericinhibition of resonance, steric inhibition of protonation, or acombination thereof of the polynucleotide, a splicing complex componentor a combination thereof. In some embodiments, binding of an SMSM to apolynucleotide or a splicing complex component decreases conformationalstability of a splice site sequence. In some embodiments, binding of anSMSM to a polynucleotide increases conformational stability of a splicesite sequence.

In some embodiments, an SMSM modulates exon skipping of a targetpolynucleotide, such as a pre-mRNA. For example, an SMSM can inhibitexon skipping of a target polynucleotide, such as a pre-mRNA. Forexample, an SMSM can promote exon skipping of a target polynucleotide,such as a pre-mRNA. In some embodiments, an SMSM modulates splicing at asplice site sequence of a polynucleotide in a cell of a subject with adisease or condition associated with exon skipping of thepolynucleotide, such as a pre-mRNA. In some embodiments, an SMSMmodulates splicing at a splice site sequence of a polynucleotide in acell of a subject with a disease or condition associated with aberrantexon skipping of the polynucleotide, such as a pre-mRNA.

In some embodiments, an SMSM modulates exon inclusion of a targetpolynucleotide, such as a pre-mRNA. For example, an SMSM can inhibitexon inclusion of a target polynucleotide, such as a pre-mRNA. Forexample, an SMSM can promote exon inclusion of a target polynucleotide,such as a pre-mRNA. In some embodiments, an SMSM modulates splicing at asplice site sequence of a polynucleotide in a cell of a subject with adisease or condition associated with exon inclusion of thepolynucleotide, such as a pre-mRNA. In some embodiments, an SMSMmodulates splicing at a splice site sequence of a polynucleotide in acell of a subject with a disease or condition associated with aberrantexon inclusion of the polynucleotide, such as a pre-mRNA.

In some embodiments, an SMSM modulates nonsense mediated degradation(NMD) of a target polynucleotide, such as a pre-mRNA. For example, anSMSM can inhibit nonsense mediated degradation (NMD) of a targetpolynucleotide, such as a pre-mRNA or an mRNA. In some embodiments, anSMSM modulates splicing at a splice site sequence of a polynucleotide ina cell of a subject with a disease or condition associated with NMD ofthe polynucleotide, such as a pre-mRNA or an mRNA.

In some embodiments, an SMSM modulates intron inclusion of a targetpolynucleotide. For example, an SMSM can inhibit intron inclusion of atarget polynucleotide, such as a pre-mRNA. For example, an SMSM canpromote intron inclusion of a target polynucleotide, such as a pre-mRNA.In some embodiments, an SMSM modulates splicing at a splice sitesequence of a polynucleotide in a cell of a subject with a disease orcondition associated with intron inclusion of the polynucleotide. Insome embodiments, the SMSM modulates splicing at a splice site sequenceof a polynucleotide in a cell of a subject with a disease or conditionassociated with intron inclusion of the polynucleotide.

In some embodiments, an SMSM modulates splicing at splice site sequenceof a polynucleotide, such as a pre-mRNA, wherein the splice sitesequence comprises a sequence selected from the group consisting ofNGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U,G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is aor c; r is a or g; v is a, c or g; k is g or u.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence NNBgunnnn, NNBhunnnn, or NNBgvnnnn. Insome embodiments, an SMSM modulates splicing of a splice site sequencecomprising a sequence NNBgurrrn, NNBguwwdn, NNBguvmvn, NNBguvbbn,NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, or NNBgvdnvn; wherein N or nis A, U, G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u;m is a or c; r is a or g; v is a, c or g; k is g or u.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2A, Table 2B, Table 2C or Table2D. In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence AAAauaagu, AAAguaagua (SEQ ID NO: 1),AAAguacau, AAAguaga, AAAguaug, AAAguaugu, AAAgugagug (SEQ ID NO: 2),AAAgugaguu (SEQ ID NO: 3), AACaugagga (SEQ ID NO: 4), AACguaagu,AACgugacu, AACgugauu, AAGaugagc, AAGauuugu, AAGgaugag, AAGgcaaaa,AAGgcaaggg (SEQ ID NO: 5), AAGgcaggga (SEQ ID NO: 6), AAGggaaaa,AAGguaugag (SEQ ID NO: 7), AAGguaaag, AAGguaaau, AAGguaaca, AAGguaacaug(SEQ ID NO: 8), AAGguaacu, AAGguaagcc (SEQ ID NO: 9), AAGguaagcg (SEQ IDNO: 10), AAGguaauaa (SEQ ID NO: 11), AAGguaaugu (SEQ ID NO: 12),AAGguaaugua (SEQ ID NO: 13), AAGguacag, AAGguacgg, AAGguacug, AAGguagacc(SEQ ID NO: 14), AAGguagag, AAGguagcg, AAGguagua, AAGguagug, AAGguauac,AAGguauau, AAGguauauu (SEQ ID NO: 15), AAGguauca, AAGguaucg, AAGguaucu,AAGguauga, AAGguaugg, AAGguaugu, AAGguauuu, AAGgucaag, AAGgucaau,AAGgucucu, AAGgucuggg (SEQ ID NO: 16), AAGgucugu, AAGgugaccuu (SEQ IDNO: 17), AAGgugagau (SEQ ID NO: 18), AAGgugaguc (SEQ ID NO: 19),AAGgugccu, AAGgugggcc (SEQ ID NO: 20), AAGgugggu, AAGguggua, AAGguguau,AAGgugucu, AAGgugugc, AAGgugugu, AAGguguua, AAGguuaag, AAGguuagc,AAGguuagug (SEQ ID NO: 21), AAGguuca, AAGguuuaa, AAGguuuau, AAGguuugg,AAGuuaagg, AAGuuaaua, AAGuuagga, AAUguaaau, AAUguaagc, AAUguaagg,AAUguaauu, AAUguaugu, AAUgugagu, AAUgugugu, ACAguaaau, ACAgugagg,ACAguuagu, ACAguuuga, ACCaugagu, ACCgugaguu (SEQ ID NO: 22), ACGauaagg,ACGcuaagc, ACGguagcu, ACGgugaac, ACGgugagug (SEQ ID NO: 23), ACUguaaau,ACUguaacu, ACUguauu, ACUgugagug (SEQ ID NO: 24), AGAguaag, AGAguaaga,AGAguaagg, AGAguaagu, AGAguagau, AGAguaggu, AGAgugaau, AGAgugagc,AGAgugagu, AGAgugcgu, AGCguaagg, AGCguaagu, AGCguacgu, AGCguaggu,AGCgugagu, AGGguaauga (SEQ ID NO: 25), AGGguagac, AGGguauau, AGGgugaau,AGGgugagg, AGGgugauc, AGGgugcaa, AGGgugucu, AGUguaagc, AGUguaagu,AGUgugagu, AGUgugaguac (SEQ ID NO: 26), AUAgucagu, AUAgugaau, AUCgguaaaa(SEQ ID NO: 27), AUCguuaga, AUGguaaaa, AUGguaacc, AUGguacau, AUGguaugu,AUGguauuu, AUGgucauu, AUGgugacc, AUUuuaagc, CAAGguaccu (SEQ ID NO: 28),CAAguaaac, CAAguaacu, CAAguaagc, CAAguaagg, CAAguaagua (SEQ ID NO: 29),CAAguaau, CAAguaugu, CAAguauuu, CAAgugaaa, CAAgugagu, CACgugagc,CACguuggu, CAGauaacu, CAGaugagg, CAGaugagu, CAGauuggu, CAGcugugu,CAGgcgagu, CAGgcuggu, CAGguaaggc (SEQ ID NO: 30), CAGguaaaa, CAGguaaag,CAGguaaccuc (SEQ ID NO: 31), CAGguaagac (SEQ ID NO: 32), CAGguaagc,CAGguaagu, CAGguaau, CAGguaaugc (SEQ ID NO: 33), CAGguaaugu (SEQ ID NO:34), CAGguacaa, CAGguacag, CAGguacagu (SEQ ID NO: 35), CAGguaccg,CAGguacug, CAGguagag, CAGguagcaa (SEQ ID NO: 36), CAGguaggagg (SEQ IDNO: 37), CAGguaggc, CAGguagguga (SEQ ID NO: 38), CAGguagua, CAGguagug,CAGguauag, CAGguauau, CAGguaucc, CAGguauga, CAGguaugg, CAGguaugu,CAGguauug, CAGgucaau, CAGgucagug (SEQ ID NO: 39), CAGgucuga, CAGgucugga(SEQ ID NO: 40), CAGgucuggu (SEQ ID NO: 41), CAGgucuuu, CAGgugacu,CAGgugagc, CAGgugaggg (SEQ ID NO: 42), CAGgugagugg (SEQ ID NO: 43),CAGgugaua, CAGgugcac, CAGgugcag, CAGgugcgc, CAGgugcug, CAGguggau,CAGgugggug (SEQ ID NO: 44), CAGgugua, CAGguguag, CAGguguau, CAGguguga,CAGgugugu, CAGguuaag, CAGguugau, CAGguugcu, CAGguuggc, CAGguuguc,CAGguuguu, CAGguuuagu (SEQ ID NO: 45), CAGguuugc, CAGguuugg, CAGuuuggu,CAUggaagac (SEQ ID NO: 46), CAUguaau, CAUguaauu, CAUguaggg, CAUguauuu,CCAguaaac, CCAgugaga, CCGguaacu, CCGgugaau, CCGgugacu, CCGgugagg,CCUauaagu, CCUaugagu, CCUguaaau, CCUguaagc, CCUguaauu, CCUgugaau,CCUgugauu, CGAguccgu, CGCauaagu, CGGguaau, CGGguauau, CGGguaugg,CGGgucauaauc (SEQ ID NO: 47), CGGgugggu, CGGguguau, CGGgugugu,CGUgugaau, CGUgugggu, CUGguauga, CUGgugaau, CUGgugaguc (SEQ ID NO: 48),CUGgugaguuc (SEQ ID NO: 49), CUGgugcau, CUGgugcuu, CUGguguga, CUGguuugu,CUGuuaag, CUGuugaga, GAAggaagu, GAAguaaac, GAAguaaau, GAAgucugg,GAAguggg, GAAgugugu, GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg,GAGCAGguaagcu (SEQ ID NO: 50), GAGcugcag, GAGgcaggu, GAGgcgugg,GAGgcuccc, GAGguggguuu (SEQ ID NO: 51), GAGguaaag, GAGguaaga, GAGguaagag(SEQ ID NO: 52), GAGguaagcg (SEQ ID NO: 53), GAGguaauac (SEQ ID NO: 54),GAGguaauau (SEQ ID NO: 55), GAGguaaugu (SEQ ID NO: 56), GAGguacaa,GAGguagga, GAGguauau, GAGguauga, GAGguaugg, GAGgucuggu (SEQ ID NO: 57),GAGgugaag, GAGgugagg, GAGgugca, GAGgugccu, GAGgugcggg (SEQ ID NO: 58),GAGgugcug, GAGguguac, GAGguguau, GAGgugugc, GAGgugugu, GAGuuaagu,GAUaugagu, GAUguaaau, GAUguaagu, GAUguaauu, GAUguaua, GAUgugacu,GAUgugagg, GAUgugauu, GCAguaaau, GCAguagga, GCAguuagu, GCGaugagu,GCGgagagu, GCGguaaaa, GCGguaauca (SEQ ID NO: 59), GCGgugacu, GCGgugagca(SEQ ID NO: 60), GCGgugagcu (SEQ ID NO: 61), GCGguggga, GCGguuagu,GCUguaaau, GCUguaacu, GCUguaauu, GGAguaag, GGAguaagg, GGAguaagu,GGAguaggu, GGAgugagu, GGAguuagu, GGCguaagu, GGCgucagu, GGGauaagu,GGGaugagu, GGGguaagug (SEQ ID NO: 62), GGGguaaau, GGGguaacu, GGGguacau,GGGgugacg, GGGgugagug (SEQ ID NO: 63), GGGgugcau, GGGguuggga (SEQ ID NO:64), GGUguaagu, GUAgugagu, GUGguaagu, GUGguaagug (SEQ ID NO: 65),GUGgugagc, GUGgugagu, GUGgugauc, GUGguugua, GUUauaagu, GUUCUCAgugug (SEQID NO: 66), GUUguaaau, GUUuugguga (SEQ ID NO: 67), uAGCAGguaagca (SEQ IDNO: 68), uGGguaccug (SEQ ID NO: 69), UAGaugcgu, UAGguaaag, UAGguaccc,UAGguaggu, UAGguauau, UAGguauc, UAGguauga, UAGguauug, UAGgucaga,UAGgugcau, UAGguguau, UCAguaaac, UCAguaaau, UCAguaagu, UCAgugauu,UCAgugug, UCCgugaau, UCCgugacu, UCCgugagc, UCUguaaau, UGAgugaau,UGGauaagg, UGGguaaag, UGGguacca, UGGguaugc, UGGguggau, UGGguggggg (SEQID NO: 70), UGGgugggug (SEQ ID NO: 71), UGGgugugg, UGGguuagu, UGUgcaagu,UGUguaaau, UGUguacau, UUAguaaau, UUCauaagu, UUGguaaag, UUGguaaca,UUGguacau, UUGguagau, UUGgugaau, UUGgugagc, UUUauaagc or UUUgugagc.

ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2,ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13,ADAMTS20, ADAMTS6, ADAMTS9, ADCY10, ADCY3, ADCY8, ADRBK2, AFP, AGL, AGT,AHCTF1, AKAP10, AKAP3, AKNA, ALAS1, ALB, ALDH3A2, ALG6, ALS2CL, AMBRA1,ANGPTL3, ANK3, ANTXR2, ANXA10, ANXA11, AP2A2, AP4E1, APC, APOA1, APOB,APOC3, APOH, AR, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP18, ARHGAP26, ARHGAP8,ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L, ASNSD1, ASPM, ATAD5, ATG16L2,ATG4A, ATM, ATP11C, ATP13A5, ATP6V1G3, ATP7A, ATP7B, ATR, ATXN2, ATXN3,B2M, B4GALNT3, BBOX1, BBS4, BCL2-like 11 (BIM), BCS1L, BMP2K, BMPR2,BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C10orf137, C11orf30,C11orf65, C11orf70, C12orf51, C13orf1, C13orf15, C14orf101, C14orf118,C15orf29, C15orf42, C15orf60, C16orf33, C16orf38, C16orf48, C18orf8,C19orf42, C11orf107, C11orf114, C11orf130, C11orf149, C11orf27,C11orf7l, C11orf87, C11orf94, C1R, C20orf74, C21orf70, C2orf55, C3,C3orf23, C4orf18, C4orf29, C5orf34, C6orf118, C8B, C8orf33, C9orf114,C9orf43, C9orf86, C9orf98, CA11, CAB39, CACHD1, CACNA1B, CACNA1C,CACNA1G, CACNA1H, CACNA2D1, CALCA, CALCOCO2, CAMK1D, CAMKK1, CAPN3,CAPN9, CAPSL, CARKD, CAT, CBX1, CBX3, CCDC102B, CCDC11, CCDC131,CCDC146, CCDC15, CCDC18, CCDC15, CCDC181, CD₁B, CD₃₃, CD₄, CD₄₆, CDC14A,CDC16, CDCl₂L5, CDC42BPB, CDCA8, CDH1, CDH10, CDH11, CDH23, CDH24, CDH8,CDH9, CDK5RAP2, CDK6, CDK8, CEL, CELSR3, CENPI, CENTB2, CENTG2, CEP110,CEP170, CEP192, CETP, CFB, CFH, CFTR, CGN, CGNL1, CHAF1A, CHD9, CHIC2,CHL1, CHM, CHN1, CLCN1, CLEC16A, CLIC2, CLINT1, CLK1, CLPB, CLPTM1,CMIP, CMYA5, CNGA3, CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2,COL12A1, COL14A1, COL15A1, COL17A1, COL19A1, COL1A1, COL1A2, COL22A1,COL24A1, COL25A1, COL29A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A5,COL4A6, COL5A2, COL6A1, COL7A1, COL9A1, COL9A2, COLQ, COMTD1, COPA,COPB2, COPS7B, COPZ2, CPSF2, CPXM2, CR1, CREBBP, CRKRS, CRYZ, CSE1L,CSTB, CSTF3, CT45-6, CUBN, CUL4B, CUL5, CXorf41, CYBB, CYFIP2, CYP17,CYP19, CYP24A1, CYP27A1, CYP3A4, CYP3A43, CYP3A5, CYP4F2, CYP4F3, DAZ2,DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D,DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DIP2A, DMD, DMTF1, DNAH3, DNAH8,DNAI1, DNAJA4, DNAJC13, DNAJC7, DNTTIP2, DOCK10, DOCK11, DOCK4, DPP3,DPP4, DPY19L2P2, DSCC1, DUX4, DVL3, DYNC1H1, DYSF, ECM2, EDEM3, EFCAB3,EFCAB4B, EFNA4, EFTUD2, EGFR, EIF3A, ELA1, ELA2A, EMCN, EMD, EML5,ENPP3, EPB41L5, EPHA3, EPHA4, EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1,ERCC8, ERGIC3, ERMN, ERMP1, ERN1, ERN2, ETS2, ETV4, EVC2, EXO1, EXOC4,F11, F13A1, F3, F5, F7, F8, FAH, FAM134A, FAM13A1, FAM13B1, FAM13C1,FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA,FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP,FECH, FEZ2, FGA, FGD6, FGFR1OP, FGFR1OP2, FGFR2, FGG, FGR, FIX, FKBP3,FLJ35848, FLJ36070, FLNA, FN1, FNBP1L, FOLH1, FOXM1, FRAS1, FUT9, FZD3,FZD6, GAB1, GALC, GALNT3, GAPDH, GART, GAS2L3, GBA, GBGT1, GCG, GCGR,GCK, GFM1, GH1, GHR, GHV, GJA1, GLA, GLT8D1, GNAS, GNB5, GOLGBl, GOLT1A,GOLT1B, GPATCH1, GPR158, GPR160, GRAMD3, GRHPR, GRIA1, GRIA3, GRIA4,GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTPBP4, HADHA, HBA2, HBB,HCK, HDAC3, HDAC5, HDX, HEPACAM2, HERC1, HEXA, HEXB, HIPK3, HLA-DPB1,HLA-G, HLCS, HLTF, HMBS, HMGCL, HNF1A, HNRNPH1, HP1BP3, HPGD, HPRT1,HPRT2, HSF2BP, HSF4, HSPA9, HSPG2, HTT, HXA, ICA1, IDH1, IDS, IFI44L,IKBKAP, IL1R2, IL5RA, IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IP04,IP08, IQGAP2, ISL2, ITFG1, ITGAL, ITGB1, ITGB2, ITGB3, ITGB4, IT1H1,ITPR2, IWS1, JAGI, JAK1, JAK2, JMJD1C, KALRN, KATNAL2, KCNN2, KCNT2,KIAA0256, KIAA0528, KIAA0564, KIAA0586, KIAA1033, KIAA1166, KIAA1219,KIAA1409, KIAA1622, KIAA1787, KIF15, KIF16B, KIF3B, KIF5A, KIF5B, KIF9,KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KLF12, KLF3, KLHL20, KLK12, KLKB1,KPNA5, KRAS, KREMEN1, KRIT1, KRT5, KRTCAP2, L1CAM, L3MBTL, L3MBTL2,LACE1, LAMA1, LAMA2, LAMA3, LAMB1, LARP7, LDLR, LENG1, LGALS3, LGMN,LHCGR, LHX6, LIMCH1, LIMK2, LMBRD1, LMBRD2, LMLN, LMNA, LMO2, LOC389634,LOC390110, LPA, LPCAT2, LPL, LRP4, LRPPRC, LRRC19, LRRC42, LRRK2, LRWD1,LUM, LVRN, LYN, LYST, MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4,MAPK8IP3, MAPK9, MAPT, MATN2, MCF2L2, MCM6, MDGA2, MEGF10, MEGF11,MEMO1, MET, MGAM, MGAT4A, MGAT5, MGC16169, MGC34774, MIB1, MIER2, MKKS,MKL2, MLANA, MLH1, MLL5, MLX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39,MRPS28, MRPS35, MS4A13, MSH2, MSMB, MST1R, MTDH, MTF2, MTHFR, MTIF2,MUC2, MUT, MVK, MYB, MYCBP2, MYH2, MYO19, MYO3A, MYO9B, MYOM2, MYOM3,NAG, NARG1, NARG2, NCOA1, NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK11, NEK5,NF1, NF2, NFE2L2, NFIA, NFIX, NFKBIL2, NFRKB, NKAIN2, NKAP, NLRC3,NLRC5, NLRP13, NLRP7, NLRP8, NME7, NOL10, NOS1, NOS2A, NOTCH1, NPM1,NR1H4, NR4A3, NRXN1, NSMAF, NSMCE2, NT5C, NT5C3, NUBP1, NUBPL, NUDT5,NUMA1, NUP160, NUP88, NUP98, NUPL1, OAT, OBFC2A, OBFC2B, OLIG2, OPA1,OPN4, OPTN, OSBPL11, OSBPL8, OSGEPL1, OTC, OXT, PADI4, PAH, PAN2,PAPOLG, PARD3, PARVB, PAWR, PBGD, PBRM1, PCBP4, PCCA, PCNX, PCOTH,PDCD4, PDE1OA, PDE8B, PDH1, PDIA3, PDK4, PDLIM5, PDS5A, PDS5B, PDXK,PDZRN3, PELI2, PGKl, PGM2, PHACTR4, PHEX, PHKB, PHLDB2, PHTF1, PIAS1,PIGF, PIGN, PIGT, PIK3C2G, PIK3CG, PIK3R1, PIP5K1A, PITRM1, PIWIL3,PKD1, PKD2, PKHD1L1, PKIB, PKLR, PKM1, PKM2, PLCB1, PLCB4, PLCG1, PLD1,PLEKHA5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2,POSTN, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1,PRDM1, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PRODH,PROSC, PROX1, PRPF40B, PRPF4B, PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1,PTEN, PTK2, PTK2B, PTPN11, PTPN22, PTPN3, PTPN4, PTPRD, PTPRK, PTPRM,PTPRN2, PTPRT, PUS10, PVRL2, PYGM, QRSL1, RAB11FIP2, RAB23, RALBP1,RALGDS, RB1CC1, RBL2, RBM39, RBM45, REC8, RFC4, RFT1, RFTN1, RHPN2,RIF1, RLN3, RMND5B, RNF11, RNF32, RNFT1, RNGTT, ROCK1, ROCK2, RP1,RP11-265F1, RP13-36C9, RP6KA3, RPAP3, RPGR, RPN1, RPS6KA6, RRM1, RRP1B,RSK2, RTEL1, RTF1, RUFY1, RYR3, SAAL1, SAE1, SBCAD, SCN11A, SCN1A,SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA, SCO1, SCYL3, SDK1, SDK2,SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3,SETD4, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A,SH3PXD2B, SH3RF2, SH3TC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2,SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC38A1, SLC38A4,SLC39A10, SLC4A2, SLC6A11, SLC6A13, SLC6A6, SLC6A8, SMARCA1, SMARCA5,SMC5, SMN2, SMTN, SNCAIP, SNRK, SNRP70, SNX6, SOD1, SPAG9, SPATA13,SPATA4, SPATS1, SPECCIL, SPINK5, SPP2, SPTA1, SRP72, SSX3, SSX5, SSX9,STAGI, STAMBPL1, STARD6, STAT6, STK17B, STX3, STXBP1, SUCLG2, SULF2,SUPT16H, SUPT6H, SV2C, SYCP1, SYCP2, SYT6, SYTL5, TAF2, TBC1D26,TBC1D29, TBC1D3G, TBC1D8B, TBCEL, TBK1, TBPL1, TCEB3, TCF12, TCP11L2,TDRD3, TEAD1, TECTB, TEK, TET2, TFRC, TG, TGM7, TGS1, THOC2, TIAL1,TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM156, TMEM194A, TMEM27, TMEM77,TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2, TOM1L1,TOM1L2, TOP2B, TP53, TP53BP2, TP53I3, TP53INP1, TP63, TRAF3IP3, TRAPPC2,TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TSC1, TSC2, TSHB,TSPAN7, TTC17, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3, TXNDC10, UBE3A,UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USP1, USP38, USP39, USP6,UTP15, UTP18, UTP20, UTRN, UTX, UTY, UVRAG, UXT, VAPA, VPS29, VPS35,VPS39, VTI1A, VTI1B, VWA3B, WDFY2, WDR16, WDR17, WDR26, WDR44, WDR67,WDTC1, WRNIP1, WWC3, XRN1, XRN2, XX-FW88277, YARS, YGM, ZBTB20, ZC3H7A,ZC3HAV1, ZC3HC1, ZFYVE1, ZNF114, ZNF169, ZNF326, ZNF365, ZNF37A, ZNF618or a ZWINT

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2A. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAAAauaagu, AAAguaagua (SEQ ID NO: 1), AAAguacau, AAAguaga, AAAguaug,AAAguaugu, AAAgugagug (SEQ ID NO: 2), AAAgugaguu (SEQ ID NO: 3),AACaugagga (SEQ ID NO: 4), AACguaagu, AACgugacu, AACgugauu, AAGaugagc,AAGauuugu, AAGgaugag, AAGgcaaaa, AAGgcaaggg (SEQ ID NO: 5), AAGgcaggga(SEQ ID NO: 6), AAGggaaaa, AAGgtatgag (SEQ ID NO: 72), AAGguaaag,AAGguaaau, AAGguaaca, AAGguaacaug (SEQ ID NO: 8), AAGguaacu, AAGguaagcc(SEQ ID NO: 9), AAGguaagcg (SEQ ID NO: 10), AAGguaauaa (SEQ ID NO: 11),AAGguaaugu (SEQ ID NO: 12), AAGguaaugua (SEQ ID NO: 13), AAGguacag,AAGguacgg, AAGguacug, AAGguagacc (SEQ ID NO: 14), AAGguagag, AAGguagcg,AAGguagua, AAGguagug, AAGguauac, AAGguauau, AAGguauauu (SEQ ID NO: 15),AAGguauca, AAGguaucg, AAGguaucu, AAGguauga, AAGguaugg, AAGguaugu,AAGguauuu, AAGgucaag, AAGgucaau, AAGgucucu, AAGgucuggg (SEQ ID NO: 16),AAGgucugu, AAGgugaccuu (SEQ ID NO: 17), AAGgugagau (SEQ ID NO: 18),AAGgugaguc (SEQ ID NO: 19), AAGgugccu, AAGgugggcc (SEQ ID NO: 20),AAGgugggu, AAGguggua, AAGguguau, AAGgugucu, AAGgugugc, AAGgugugu,AAGguguua, AAGguuaag, AAGguuagc, AAGguuagug (SEQ ID NO: 21), AAGguuca,AAGguuuaa, AAGguuuau, AAGguuugg, AAGuuaagg, AAGuuaaua, AAGuuagga,AAUguaaau, AAUguaagc, AAUguaagg, AAUguaauu, AAUguaugu, AAUgugagu,AAUgugugu, ACAguaaau, ACAgugagg, ACAguuagu, ACAguuuga, ACCaugagu,ACCgugaguu (SEQ ID NO: 22), ACGauaagg, ACGcuaagc, ACGguagcu, ACGgugaac,ACGgugagug (SEQ ID NO: 23), ACUguaaau, ACUguaacu, ACUguauu, ACUgugagug(SEQ ID NO: 24), AGAguaaga, AGAguaagg, AGAguaagu, AGAguagau, AGAguaggu,AGAgugaau, AGAgugagc, AGAgugagu, AGAgugcgu, AGCguaagg, AGCguaagu,AGCguacgu, AGCguaggu, AGCgugagu, AGGguaauga (SEQ ID NO: 25), AGGguagac,AGGguauau, AGGgugaau, AGGgugagg, AGGgugauc, AGGgugcaa, AGGgugucu,AGUguaagc, AGUguaagu, AGUgugagu, AGUgugaguac (SEQ ID NO: 26), AUAgucagu,AUAgugaau, AUCgguaaaa (SEQ ID NO: 27), AUCguuaga, AUGguaaaa, AUGguaacc,AUGguacau, AUGguaugu, AUGguauuu, AUGgucauu, AUGgugacc, AUUuuaagc,CAAGguaccu (SEQ ID NO: 28), CAAguaaac, CAAguaacu, CAAguaagc, CAAguaagg,CAAguaagua (SEQ ID NO: 29), CAAguaau, CAAguaugu, CAAguauuu, CAAgugaaa,CAAgugagu, CACgugagc, CACguuggu, CAGauaacu, CAGaugagg, CAGauuggu,CAGcugugu, CAGgcuggu, CAGgtaaggc (SEQ ID NO: 73), CAGguaaaa, CAGguaaag,CAGguaaccuc (SEQ ID NO: 31), CAGguaagac (SEQ ID NO: 32), CAGguaagc,CAGguaagu, CAGguaau, CAGguaaugc (SEQ ID NO: 33), CAGguaaugu (SEQ ID NO:34), CAGguacaa, CAGguacag, CAGguacagu (SEQ ID NO: 35), CAGguaccg,CAGguacug, CAGguagag, CAGguagcaa (SEQ ID NO: 36), CAGguaggagg (SEQ IDNO: 37), CAGguaggc, CAGguagguga (SEQ ID NO: 38), CAGguagua, CAGguagug,CAGguauag, CAGguauau, CAGguaucc, CAGguauga, CAGguaugg, CAGguaugu,CAGguauug, CAGgucaau, CAGgucagug (SEQ ID NO: 39), CAGgucuga, CAGgucugga(SEQ ID NO: 40), CAGgucuggu (SEQ ID NO: 41), CAGgucuuu, CAGgugagc,CAGgugaggg (SEQ ID NO: 42), CAGgugagugg (SEQ ID NO: 43), CAGgugaua,CAGgugcac, CAGgugcag, CAGgugcgc, CAGgugcug, CAGguggau, CAGgugggug (SEQID NO: 44), CAGgugua, CAGguguag, CAGguguau, CAGguguga, CAGgugugu,CAGguuaag, CAGguugau, CAGguugcu, CAGguuggc, CAGguuguc, CAGguuguu,CAGguuuagu (SEQ ID NO: 45), CAGguuugc, CAGguuugg, CAGuuuggu, CAUggaagac(SEQ ID NO: 46), CAUguaau, CAUguaauu, CAUguaggg, CAUguauuu, CCAguaaac,CCAgugaga, CCGguaacu, CCGgugaau, CCGgugacu, CCGgugagg, CCUauaagu,CCUaugagu, CCUguaaau, CCUguaagc, CCUguaauu, CCUgugaau, CCUgugauu,CGAguccgu, CGCauaagu, CGGguaau, CGGguauau, CGGguaugg, CGGgucauaauc (SEQID NO: 47), CGGgugggu, CGGguguau, CGGgugugu, CGUgugaau, CGUgugggu,CUGguauga, CUGgugaau, CUGgugaguc (SEQ ID NO: 48), CUGgugaguuc (SEQ IDNO: 49), CUGgugcau, CUGgugcuu, CUGguguga, CUGguuugu, CUGuuaag,CUGuugaga, GAAggaagu, GAAguaaac, GAAguaaau, GAAgucugg, GAAguggg,GAAgugugu, GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg, GAGCAGguaagcu(SEQ ID NO: 50), GAGcugcag, GAGgcaggu, GAGgcgugg, GAGgcuccc, GAGgtgggttt(SEQ ID NO: 74), GAGguaaag, GAGguaaga, GAGguaagag (SEQ ID NO: 52),GAGguaagcg (SEQ ID NO: 53), GAGguaauac (SEQ ID NO: 54), GAGguaauau (SEQID NO: 55), GAGguaaugu (SEQ ID NO: 56), GAGguacaa, GAGguagga, GAGguauau,GAGguauga, GAGguaugg, GAGgucuggu (SEQ ID NO: 57), GAGgugaag, GAGgugagg,GAGgugca, GAGgugccu, GAGgugcggg (SEQ ID NO: 58), GAGgugcug, GAGguguac,GAGguguau, GAGgugugc, GAGgugugu, GAGuuaagu, GAUaugagu, GAUguaaau,GAUguaagu, GAUguaauu, GAUguaua, GAUgugacu, GAUgugagg, GAUgugauu,GCAguaaau, GCAguagga, GCAguuagu, GCGaugagu, GCGgagagu, GCGguaaaa,GCGguaauca (SEQ ID NO: 59), GCGgugacu, GCGgugagca (SEQ ID NO: 60),GCGgugagcu (SEQ ID NO: 61), GCGguggga, GCGguuagu, GCUguaaau, GCUguaacu,GCUguaauu, GGAguaagg, GGAguaagu, GGAguaggu, GGAgugagu, GGAguuagu,GGCguaagu, GGCgucagu, GGGauaagu, GGGaugagu, GGGgtaagtg (SEQ ID NO: 75),GGGguaaau, GGGguaacu, GGGguacau, GGGgugacg, GGGgugagug (SEQ ID NO: 63),GGGgugcau, GGGguuggga (SEQ ID NO: 64), GGUguaagu, GUUCUCAgugug (SEQ IDNO: 66), UCAgugug, GUAgugagu, GUGguaagu, GUGguaagug (SEQ ID NO: 65),GUGgugagc, GUGgugagu, GUGgugauc, GUGguugua, GUUauaagu, GUUguaaau,GUUuugguga (SEQ ID NO: 67), UAGCAGguaagca (SEQ ID NO: 68), TGGgtacctg(SEQ ID NO: 76), UAGaugcgu, UAGguaaag, UAGguaccc, UAGguaggu, UAGguauau,UAGguauc, UAGguauga, UAGguauug, UAGgucaga, UAGgugcau, UAGguguau,UCAguaaac, UCAguaaau, UCAguaagu, UCAgugauu, UCCgugaau, UCCgugacu,UCCgugagc, UCUguaaau, UGAgugaau, UGGauaagg, UGGguaaag, UGGguacca,UGGguaugc, UGGguggau, UGGguggggg (SEQ ID NO: 70), UGGgugggug (SEQ ID NO:71), UGGgugugg, UGGguuagu, UGUgcaagu, UGUguaaau, UGUguacau, UUAguaaau,UUCauaagu, UUGguaaag, UUGguaaca, UUGguacau, UUGguagau, UUGgugaau,UUGgugagc, UUUauaagc or UUUgugagc.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2B. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAAAauaagu, AAGaugagc, AAGauuugu, AAGgaugag, AAGgcaaaa, AAGuuaagg,AAGuuaaua, AAGuuagga, ACCaugagu, ACGauaagg, ACGcuaagc, AGGguauau,AGGgugagg, AGGgugauc, AGGgugucu, AUGgugacc, AUUuuaagc, CAAgugagu,CACgugagc, CACguuggu, CAGauaacu, CAGaugagg, CAGaugagu, CAGauuggu,CAGcugugu, CAGgcgagu, CAGgcuggu, CAGgugacu, CAGguugau, CAGguugcu,CAGguuggc, CAGguuguu, CAGuuuggu, CAUguaggg, CAUguauuu, CCGgugaau,CCUauaagu, CCUaugagu, CCUgugaau, CGCauaagu, CGGguguau, CUGuuaag,CUGuugaga, GAAggaagu, GAAguaaau, GAAgucugg, GAAguggg, GAAgugugu,GAAuaaguu, GACaugagg, GAGaucugg, GAGaugagg, GAGgcaggu, GAGgcgugg,GAGgcuccc, GAGguaaga, GAGguagga, GAGgugagg, GAGuuaagu, GAUaugagu,GAUaugagu, GCAguagga, GCGaugagu, GCGgagagu, GCGgugacu, GCGguuagu,GCUguaacu, GGGaugagu, GUAgugagu, GUGgugagc, GUGgugauc, UAGaugcgu,UGGauaagg, UGGguacca, UGGguggau, UGGgugggug (SEQ ID NO: 71), UGUgcaagu,UUCauaagu, UUGguaaca, UUUauaagc or UUUgugagc.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2C or Table 2D. In someembodiments, an SMSM modulates splicing of a splice site sequencecomprising a sequence NGAguaag.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2C. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceAGAguaag.

In some embodiments, an SMSM modulates splicing of a splice sitesequence comprising a sequence of Table 2D. In some embodiments, an SMSMmodulates splicing of a splice site sequence comprising a sequenceGGAguaag.

TABLE 2A Exemplary targets Splice Site SEQ Gene Disease  Sequence ID NO:Description Exon ABCA4 Stargardt disease, Macular GAGguaaagNon-mutated 5' bulge  3 Degeneration, Age-Related CGGguauggNon-mutated 5' bulge  4 AGUguaagc Non-mutated 5' bulge 13 CCAguaaacIVS20 + 5G>A 20 CAGgugcac IVS28 + 5G>A 28 AUGguacau IVS40+5G>A 40AGAguaggu Non-mutated 5' bulge  6 AAGguacug Non-mutated 5' bulge 11GGAguaggu Non-mutated 5' bulge 20 ABCD1 X-linked adrenoleukodystrophy GAAguggg IVS1 - 1G>A  1 (X-ALD) ACADM Medium-chain acyl-coA DH AAGguaaauIVS7 + 6G>U   8 deficiency Mutated 5' bulge ACADSB2-methylbutyryl-CoA dehydrogenase GGGgugcau IVS3 + 3A>G  3 deficiencyADA Adenosine deaminase deficiency CCAgugaga IVS5 + 6U>A  5 ADAMTS13Thrombotic thrombocytopenic AGGguagac IVS13 + 5G>A 13 purpura AGLGlycogen Storage Disease Type III GGCguaagu Non-mutated 5' bulge  1CUGguauga IVS6 + 3A>G  6 AAGguagug Non-mutated 5' bulge 28 AGAguaaguNon-mutated 5' bulge 31 AGT Treatment Resistant Hypertension AAGguaagcc9 Non-mutated 5'ss   1 ALB Analbuminemia AACaugagga 4 c.1652 + G>A 12ALDH3A2 Cancer, non-small cell lung cancer, CAGgucuggu 41Non-mutated 5' bulge  2 Sjőgren-Larrson syndrome AAGguuuau IVS5 + 5G>A 5 ALG6 ALG6-congenital disorder of UGUguaaau IVS5 + 5G>A  3glycosylation, ALG6-CDG ANGPTL3 Lipid disorders, Rare hyperlipidemias,AAAguaagua 1 Non-mutated 5'ss  1 Nonalcoholic fatty liver disease(NAFLD), Metabolic complications, Homozygous familialhypercholesterolemia (HoFH), Familial chylomicronemia syndrome (FCS) APCColorectal cancer, Familial CAAguaugu IVS9 + 3A>G  9adenomatous polyposis CAAguauuu IVS9 + 5G>G  9 CAGguauau 69 IVS14 + 3A>G14 APOA1 UGGguaccug Non-mutated 5'ss  1 APOBFamilial hypercholesterolemia, AGAguaagu Non-mutated 5' bulge 13hypercholesterolemia Homozygous AAGgcaaaa IVS24 + 2U>C 24hypobetalipoproteinemia, familial hypercholesterolemia APOC3Familial Chylomicronemia Syndrome CAGguaaugc 33 Non-mutated 5'ss  1(FCS) and familial partial lipodystrophy (FPL) ARAndrogen Sensitivity, prostate cancer CUGuuaag IVS4 + 1G>U  4 UUAguaaauIVS6 + 5G>A  6 ATM Ataxia-Telangiectasia, cancer AAGguaguaNon-mutated 5' bulge  2 UAGguauau IVS7 + 5∧dG>A  7 CAGguacagNon-mutated 5' bulge  8 UUGguaaag Non-mutated 5' bulge  9 AAGguuuaaIVS9 + 3A>U  9 AUCguuaga IVS21 + 3A>U 21 AUCgguaaaa 27 IVS21 + 5∧dG>A 21AAGgucucu Non-mutated 5' bulge 35 GAGguaaugu 56 Non-mutated 5' bulge 38CAGauaacu IVS45 + 1G>A 45 GAGguaaag Non-mutated 5' bulge 61 ATP7AOccipital Horn Syndrome, Menkes AAGguaaugu 12 Non-mutated 5' bulge  3Disease Occipital Horn Syndrome GUUguaaau IVS6 + 5G>A 6                        Menkes Disease GUUauaagu IVS6 + 1G>A  6Occipital Horn Syndrome, Menkes AAGguaaag Non-mutated 5' bulge 10Disease Occipital horn syndrome AAGguuaag IVS10 + 3A>U  1Mutated 5' bulge Menkes Disease CAGgucuuu IVS11 + 3A>C(mousemodel), consistent   11 with patient Occipital Horn Syndrome, MenkesCAAguaaac IVS17 + 5G>A 17 Disease CUGguuugu IVS21 + 3A>U 21 ATP7BWilson's disease AAAgugaguu 3 Non-mutated 5'ss  1 ATR Seckel syndrome 1CAGguauug Non-mutated 5' bulge 19 CAGgucuga Non-mutated 5' bulge 28ATXN2 Spinocerebellar ataxia type 2 (SCA2), CAGgugggug 44Non-mutated 5'ss  1 ALS GAGguggguuu 51 Non-mutated 5'ss  5 ATXN3Spinocerebellar ataxia type 3 (SCA3) AAAgugagug 2 Non-mutated 5'ss  1B2M Cancer, colorectal cancer AGCgugagu Non-mutated 5' bulge  1BCL2-like 11 Autoimmune disease, tumor AGGguaauga 25 Non-mutated 5'ss3,4 (BIM) development, Chronic Myeloid GUUuugguga 67Leukemia drug resistance BMP2K Cancer CAAguaagg Mutation inducing loss  14 of UlsnRNA affinity BRCA1 Breast Cancer UGGguaaagNon-mutated 5' bulge  1 AAGguguau IVS5 + 3A>G  5 AGGguauau IVS5 + 2A>G 5 AAGgugugc IVS13 + 6U>C 13 UUUgugagc IVS16 + 6U>C 16 UCUguaaauIVS18 + 5G>A 18 ACAguaaau IVS22 + 5G>A 22 BRCA2 Breast Cancer CAGgugugaIVS5 + 3A>G  5 UAGguauug Non-mutated 5' bulge 14 CAGguaugaNon-mutated 5' bulge 19 BTK Isolated growth hormone deficiency AAGgugguaNon-mutated 5' bulge  2 type III, X-linked GAAguaaac IVS6 + 5G>A  6agammaglobulinemia (XLA), Cancer, GAUgugagg IVS14 + 6U>G 14Autoimmune disorders C3 Hereditary C3 deficiency UGGauaagg IVS18 + 1G>A18 CACNA1B Pain, tactile neuropathic allodynia GUGguaagug 65Non-mutated 5'ss 37a AAGguagacc 14 Non-mutated 5'ss 37b CACNA1CType 1 Timothy's syndrome GAGCAGguaagcu 50 G406R(G>A)  8aType 2 Timothy's syndrome UAGCAGguaagca 68 G406R(G>A)  8 GUUCUCAgugug 66G402R(G>A)  8 CALCA CGRP-related migraines CAUggaagac 46Non-mutated 5'ss  4 CAT Acatalasemia and Pityriasis UUGguagauIVS4 + 5G>A  4 Versicolor, Autoimmune disease, cancer CD33Alzheimer's disease, acute myeloid CAGgugagugg 43 Non-mutated 5'ss  1leukemia CD46 Autoimmune disorders, cancer, CAGguuuagu 45Non-mutated 5'ss  7 atypical hemolytic uremic syndrome CAGguuuagu 45Non-mutated 5'ss  8 (aHUS), multiple sclerosis, AAGguaucuNon-mutated 5'ss 13 rheumatoid arthritis, age-relatedmacular degeneration, asthma CDH1 Cancer, hereditary diffuse gastricCAGguggau IVS14 + 5G>A 14 cancer syndrome CDH23Usher Syndrome and Nonsyndromic ACGgugaac IVS51 + 5G>A 51 DeafnessAGCguaagg Non-mutated 5' bulge 54 CFB Hemolytic Uremic Syndrome,GAGguaagcg 53 Non-mutated 5'ss  1 (ComplementAtypical 4 and Complement Factor B factor B) Deficiency CFTRCystic Fibrosis CAUguaau -1G>U   8 Mutated 5'bulge AAAguaug -1G>A 19Mutated 5'bulge AAGuuaaua IVS4 + 1G>U  4 ACAguuagu IVS6b + 3∧d 6bCAGguaaugu 34 Non-mutated 5' bulge  8 AAAguaugu c.1766 - 1G>A 12AAUguaugu c.1766 - 1G>U 12 AAGguauuu IVS12 + 5G>U 12 AAGguguguc.1766 + 3A>G 12 AAGgucugu c.1766 + 3A>C 12 AAGguaugaNon-mutated 5' bulge 19 CACgugagc IVS20 - 1G>C 20 CHM ChoroideremiaUAGgucaga IVS13 + 2A>C 13 CLCN1 Myotonia congenita CAGguuuaagIVS1 + 3A>U  1 Mutated 5' bulge COL11A1Stickler syndrome, Cancer, Marshall GAGguaauac 54 Non-mutated 5' bulge 7 syndrome AGCguaagu Non-mutated 5' bulge  8 AGAguaaguNon-mutated 5' bulge 29 AAGguauca Non-mutated 5' bulge 34 GGCguaaguNon-mutated 5' bulge 50 GGCgucagu IVS18 + 301G>A 18  5 GGAguaaguNon-mutated 5' bulge 64 COL11A2 Otospondylomegaepiphyseal CCUgugaauIVS53 + 5G>A 53 Dysplasia, Stickler syndrome COL1A1Severe III osteogenesis imperfecta GGAguaagu Non-mutated 5' bulge  5UCAguaaac IVS8 + 5G>A  8 CCUaugagu IVS8 + 1G>A  8 AGAgugaguNon-mutated 5' bulge 11 GCUguaaau IVS14 + 5G>A 14 AGCgugaguNon-mutated 5' bulge 19 AGAguaagu Non-mutated 5' bulge 30 COL1A2Osteogenesis imperfecta AGAguagau IVS21 + 5G>A 21 Mutated 5' bulgeGAUguaaau IVS9 + 5G>A  9 AGAguaggu Non-mutated 5' bulge 21 AGAguaaguNon-mutated 5' bulge 23 CGGgugggu IVS26 + 3A>G 26 AGAguaaguNon-mutated 5' bulge 30 CGUgugaau IVS33 + 5G>A 33 CGUgugggu IVS33 + 4G>G33 GCUguaaau IVS40 + 5G>A 40 COL2A1 Chondrodysplasias, familialGUGguugua Non-mutated 5' bulge  2 osteoarthritis GGAguaaguNon-mutated 5' bulge  7 AGAguaagu Non-mutated 5' bulge 13 CCUgugauuIVS20 + 5G>U 20 UCUguaaau IVS20 + 5G>A 24 AGAguaagu Non-mutated 5' bulge49 COL3A1 Ehlers-Danlos syndrome  CCUguaagc IVS7 + 6U>C  7 UCAguaaauIVS8 + 5G>A  8 AGAguaagu Non-mutated 5' bulge 10 GCAguuagu IVS14 + 3G>U14 Ehlers-Danlos syndrome IV CCUauaagu IVS16 + 1G>A 16 CGCauaaguIVS20 + 1G>A 20 Ehlers-Danlos syndrome GAUgugauu IVS25 + 5G>U 25ACUguaaau IVS27 + 5G>A 27 ACUguauu IVS27 + 5G>U 27 AAGguaguaNon-mutated 5' bulge 29 GCUguaauu IVS37 + 5G>U 37 CCUgugauu IVS38 + 5G>A38 CCUguaauu IVS38 + 5G>U 38 GAUgugacu IVS42 + 5G>C 42Ehlers-Danlos syndrome IV GAUaugagu IVS42 + 1G>A 42Ehlers-Danlos syndrome CCUguaauu IVS45 + 5G>A 45 AGAguaaguNon-mutated 5' bulge 46 COL4A5 Alport syndrome AGAguaaguNon-mutated 5' bulge  4 AGAguaagu Non-mutated 5' bulge 15 AAGgucuggg 16Non-mutated 5' bulge 28 CAGgugcug Non-mutated 5' bulge 39 CAGguaaagNon-mutated 5' bulge 52 COL6A1 Mild Bethlem myopathy GGGaugaguIVS3 + 1G>A  3 Autosomal-recessive isolated AAGguacggNon-mutated 5' bulge  4 dystonia, dystonia CAGguuaagNon-mutated 5' bulge  6 AAGguacgg Non-mutated 5' bulge 14 AAAguacauIVS29 + 5G>A 29 AGUguaagu Non-mutated 5' bulge 38 COL7A1Recessive dystrophic epidermolysis AGGgugauc IVS3 - 2A>G  3 bullosaDominant dystrophic epidermolysis CAGguauag Non-mutated 5' bulge 23bullosa CAGguuugg Non-mutated 5' bulge 24 CAGguuugg Non-mutated 5' bulge27 AGGguuugg Non-mutated 5' ss 73 Recessive dystrophic epidermolysisGUAgugagu IVS95 - 1G>A 95 bullosa COL9A2 Multiple epiphyseal dysplasiaCCGgugagg IVS3 + 6U>G  3 CCGgugacu IVS3 + 5G>C  3 COLQCongenital acetylcholinesterase UGGguggggg 70 IVS16 + 3A>G 16 deficiencyCREBBP Rubinstein-Taybi syndrome AAGguuca +3A>U 18 Mutated 5' bulge CSTBEpilepsy:progressive myoclonus AAAguaga -1G>A  2 Mutated 5' bulge CUL4BX-linked intellectual disability, cancer CAGguaaaa Non-mutated 5' bulge14 CYBB X-linked chronic granulomatous GGGguaaau IVS2 + 5G>A  2 diseaseGCGguaaaa IVS3 + 5G>A  3 AAGguuagc IVS5 + 3A>U  5 UCAgugaau IVS6 + 5G>A 6 CYP17 Congenital adrenal hyperplasia and UCAgugauu IVS2 + 5G>U  217-hydroxylase deficiency CUGgugaau IVS7 + 5G>A  7 CYP19Placental aromatase deficiency UGUgcaagu IVS6 + 2U>C  6 CYP27A1Cerebrotendineous xanthomatosis AACgugauu IVS7 + 5G>U  7 GAGguaggaIVS6 - 2C>A  6 GCAguagga IVS6 - 1G>A  6 DES Desmin-related myopathyGAGguguac IVS3 + 3A>G  3 DGAT2 Nonalcoholic steatohepatitis (NASH)GGGgugagug 63 Non-mutated 5' ss  1 DMD Duchenne's muscular dystrophy,GAUguaagu Non-mutated 5' bulge  5 Duchenne and Becker muscular CAGguaaagNon-mutated 5' bulge  8 dystrophy CAGgugugu Non-mutated 5' bulge 14AUGgucauu IVS19 + 3A>C 19 AGAguaaga Non-mutated 5' bulge 24 AAGggaaaaIVS26 + 2U>G 26 CAGguauau c.4250U>A 31 CAGguauau Non-mutated 5' bulge 31AAGguaugag 7 Non-mutated 5' ss 51 CAAguaacu IVS62 + 5G>C 62 GCUguaacuIVS64 + 5G>C 64 GCUguaacu IVS64 + 5G>C 64 GAUguaauu IVS66 + 5G>U 66CCGguaacu IVS69 + 5G>C 69 AACgugacu IVS70 + 5G>C 70 DUX4 FSHD GGGguuggga64 Non-mutated 5' ss  1 DYSF Limb Girdle Muscular Dystrophy 2B,AGAgugcgu Non-mutated 5' bulge 13 Miyoshi myopathy, Miyoshi MuscularUGUguacau IVS45 + 5G>A    45 Dystrophy 1 EGFR Cancer AACguaaguNon-mutated 5' ss  4 ACAguuuga Non-mutated 5' bulge  9 GUGgugaguNon-mutated 5' bulge 22 EMD Emery-Dreifuss muscular dystrophy UAGguacccIVS1 + 5G>C     1 ETV4 Ovarian Cancer GAGcugcag Non-mutated 5' bulge  5F13A1 Cancer UUGgugagc IVS3 + 6C>U     3 UUGgugaau IVS3 + 5G>A     3 F5Factor V deficiency AAGguaacu Non-mutated 5' bulge  1 CAUguauuuIVS10 - GC>U    10 AAGguuugg Non-mutated 5' bulge 13 UGGguuaguIVS19 + 3A>U    19 AAGgucaag Non-mutated 5' bulge 23 AAGguagagNon-mutated 5' bulge 24 F7 Factor VII deficiency UGGguggauIVS7 + 5G>A     7 UGGgugggug 71 IVS7 + 7A>G     7 UGGguaccaIVS7del[+3:+6]     7 F8 Hemophilia A AGGgugaau IVS3 + 5G>A     3CAGgugugu IVS6 + 3A>G     6 CAGguguga IVS14 + 3A>G    14 AUAgugaauIVS19 + 5G>A    19 AUGguauuu IVS22 + 5G>U    22 AUAgucaguIVS23 + 3A>C    23 F11 Factor XI, clotting disorders CAGguacagu 35Non-mutated 5' ss  1 FAH Tyrosinemia type I, Chronic AAGguauguNon-mutated 5' bulge 11 Tyrosinemia Type 1 CCGugaau IVS12 + 5G>A    12FANCA Fanconi Anemia AGAguaaga Non-mutated 5' bulge  4 AAGguagcgNon-mutated 5' bulge  6 CUGgugcau IVS7 + 5G>A     7 CUGgugcuuIVS7 + 5G>U     7 GAGgugcug Non-mutated 5' bulge 10 CGAguccguIVS16 + 3A>C    16 FANCC Fanconi anemia AAUgugugu IVS4 + 4A>U   4 FANCGFanconi Anemia, Complementation CAGgugaua IVS4 + 3A>G     4Group G and Fanconi Anemia, Complementation Group A FBN1 Marfan SyndromeUUGguacau IVS11 + 5G>A    11 GAGguaugg Non-mutated 5' bulge 13AAGguaauaa 11 Non-mutated 5' bulge 14 CAGgucaau IVS25 + 5G>A    25CAUguaauu IVS37 + 5G>U   37 UAGgugcau IVS46 + 5G>A  46 UAGaugcguIVS46 + 1G>A   46 AAGguaaag Non-mutated 5' bulge 60 FECHErythropoietic protoporphyria UAGguauc -3A>U 10 Mutated 5' bulgeGAGguauga Non-mutated 5' bulge  2 Non-mutated 5' bulge  4 IVS10 + 3A>G  10 Non-mutated 5' bulge 10 FGA Common congenital afibrinogenemiaUGGgugugg IVS1 + 3A>G    1 GAGuuaagu IVS4 + 1G>U    4 FGFR2Craniosynostosis syndromes, cancer AGAguaacu Non-mutated 5' bulge  3CAGguguau IVS3c + 3A>G    3c FGG Dysfibrinogenaemia GCAguaaauIVS1 + 5G>A    1 CAAgugaaa IVS3 + 5G>A    3 FIX Haemophilia B deficiencyCGGgucauaauc 47 c.519A>G  5 (coagulation factor IX deficiency) FLNAX-linked cardiac valvular dysplasia AGAguaagu Non-mutated 5' bulge 19FOXM1 Cancer AAGguaaugu 12 Non-mutated 5' bulge  4 UCAguaaguNon-mutated 5' bulge  9 FRAS1 Fraser syndrome AAGguacggNon-mutated 5' bulge  3 GGAgugagu Non-mutated 5' bulge  5 AAGguauuuNon-mutated 5' bulge  8 AAGguaucg Non-mutated 5' bulge 17 AGCguagguNon-mutated 5' bulge 22 AGAguaagu Non-mutated 5' bulge 24 CAGguacaaNon-mutated 5' bulge 53 GALC NASH GGAguuagu Non-mutated 5' bulge  5 GBAGaucher's disease GAGguaagag 52 Non-mutated 5' ss  2 GCGR DiabetesGCGgugagca 60 Non-mutated 5' ss  1 GH1 Growth hormone deficiencyUCCgugagc IVS3 + 6U>C    3 UCCgugaau IVS3 + 5G>A    3 UCCgugacuIVS3 + 5G>C    3 GGGgugacg IVS4 + 5G>C    4 GGGgugacg IVS4 + 5G>A    4GHR Acromegaly GGGguaagug 62 Non-mutated 5' ss  1 GHVMutation in placenta UUUauaagc IVS2 + 1G>A    2 GLA Fabry's diseaseAAGgugagau 18 Non-mutated 5' ss  4 HADHATrifunctional protein deficiency or AAGgugucu IVS3 + 3A>G    3 LCHADAGUguaagu Non-mutated 5' bulge 18 HBA2 Alpha-thalassemia GAGgcucccIVS1 del[+2:+6]    1 HBB Beta-thalassemia CAGguuguu IVS1 + 5G>U    1CACguuggu IVS1 - 1G>C    1 CAGguuggc IVS1 + 6U>C    1 CAGauugguIVS1 + 1G>A    1 CAGuuuggu IVS1 + 1G>U    1 CAGgcuggu IVS1 + 2U>C    1CAGguugau IVS1 + 5G>A    1 CAGguugcu IVS1 + 5G>C    1 AGGgugucuIVS2del[+4:+5]    2 HEXA Tay-Sachs Syndrome ACAguaaau IVS4 + 5G>A    4CUGguguga IVS8 + 3A>G    8 GACaugagg IVS9 + 1G>A    9 HEXBSandhoff disease UUGguaaca IVS8 + 5G>C    8 HLCSHolocarboxylase synthetase AAGgucaau IVS10 + 5G>A   10 deficiency HMBSAcute intermittent porphyria GCGguuagu IVS1 + 3G>U    1 GCGgugacuIVS1 + 5G>C    1 HMGCL Hereditary HL deficiency ACGcuaagc IVS7 + 1G>C   7 HNF1A diabetes AGCguaagu Non-mutated 5' bulge  2 HPRT1Somatic mutations in kidney tubular GUGgugagc IVS1del[-2:+34]    1epithelial cells GUGgugauc IVS1 + 5G>U    1 Lesch-Nyhan syndromeGAAggaagu IVS5 + 2U>G    5 GAAgugugu IVS5 + 3:4AA>GU    5 GAAguaaauIVS5+5G>A    5 GAAuaaguu IVS5del[G1]   5 ACUguaaau IVS7 + 5G>A    7Hypoxanthine ACUguaacu IVS7 + 5G>C    7phosphoribosyltransferase deficiency AAUguaagc IVS8 + 6U>C    8Mutation inducing loss   of U1snRNA affinity AAUguaagg IVS8 + 6U>G    8AAUguaaau IVS8 + 5G>A    8 AAUguaauu IVS8 + 5G>U   HPRT2Primary hyperthyroidism GGGauaagu IVS1 + 1G>A    1 HSF4Congenital cataracts CAGguagug IVS12 + 4A>G   12 HSPG2Schwartz-Jampel syndrome type 1 AGAgugagu Non-mutated 5' ss 30 AGAguaaguNon-mutated 5' ss 40 CAGguacag Non-mutated 5' ss 61 HTTHuntington's disease CAGguacug Non-mutated 5' ss 25 AAGguaaauNon-mutated 5' ss 32 AGAguaagu Non-mutated 5' ss 51 CUGgugaguc 48Non-mutated 5' ss 52 ACCgugaguu 22 Non-mutated 5' ss  1 IDH1 GliomasCAGguaaccuc 31 Non-mutated 5' ss  1 ACUgugagug 24 Non-mutated 5' ss  1IDS Mucopolysaccharidosis type II AUGguaacc IVS7 + 5G>C    7(Hunter syndrome) AUUuuaagc IVS7 - 1:1GG>UU    7 IKBKAPFamilial Dysautonomia, CAAguaagc IVS20 + 6U>C 20 DysautonomiaMutation inducing loss  of U1snRNA affinity CAGguaugu Non-mutated 5' ss27 AGCguacgu Non-mutated 5' ss 33 IL7RAEncodes IL7RA, Multiple sclerosis AAGgugaccuu 17 Non-mutated 5' ss  6INSR Breast Cancer GGCguaagu Non-mutated 5' bulge  7 AGUguaaguNon-mutated 5' bulge 20 ITGB2 Leukocyte adhesion deficiency UUCauaaguIVS7 + 1G>A    7 ITGB3 Glanzmann thrombasthenia GAUaugagu IVS4 + 1G>A   4 ITGB4 Epidermolysis bullosa with congenital GAGgugccuNon-mutated 5' bulge  4 pyloric atresia CAGguagua Non-mutated 5' bulge33 JAG1 Alagille syndrome CGGgugugu IVS11 + 1A>G   11 AGAgugaguNon-mutated 5' bulge 18 KLKB1 Hereditary angioedema CAGguagcaa 36Non-mutated 5' ss  1 KRAS Cancer CAGguaagu Splice switching on  4aisoforms KRT5 Dowling-Meara epidermolysis AAGaugagc IVS1 + 1G>A  1bullosa simplex L1CAM Cancer AAUgugagu Non-mutated 5' bulge  2 AGAguaagaNon-mutated 5' bulge 14 CAGgugagc Non-mutated 5' bulge 27 CAGguaaggc 30Non-mutated 5' ss  1 LAMA2 Muscular dystrophy: merosin GAGgugca +3A>G  1deficient Mutated 5' bulge LAMA3 Cancer, Junctional epidermolysisCAGguaaag Non-mutated 5' bulge 16 bullosa AAGguaaugu 12Non-mutated 5' bulge 26 CAGguagug Non-mutated 5' bulge 27 AGCguaaguNon-mutated 5' bulge 31 CAGguaccg Non-mutated 5' bulge 40 AAGguaaugu 12Non-mutated 5' bulge 45 AGAgugagu Non-mutated 5' bulge 50 GAGguacaaNon-mutated 5' bulge 57 UGGguaugc Non-mutated 5' bulge 64 LDLRFamilial hypercholesterolemia GAGgcgugg IV12 + 2U>C 12 LGALS3 NASHGCGgugagcu 61 Non-mutated 5' ss  1 LMNA Hutchinson-Gilford progeriaCAAgugagu c.1968 - 1G>A 10 syndrome(HGPS) LPAHyperlipoproteinemia, Type Iii and CAGguaagac 32 Non-mutated 5' ss  1Familial Hyperlipidemia LPL Familial hypercholesterolemia ACGauaaggIVS2 + 1G>A  2 LRRK2 Parkinson's disease GCGguaauca 59 Non-mutated 5' ss 1 AAGguaacaug 8 Non-mutated 5' ss 31 CAGguagguga 38 Non-mutated 5' ss41 MADD Cancer, Glioblastoma AAGguacag Non-mutated 5' bulge  3 AAGguggguNon-mutated 5' bulge 16 AGAguaagg Non-mutated 5' bulge 21 MAPTFrontotemporal Dementia AGUguaagu IVS10 + 3G>A 10Alzheimer's disease, Frontotemporal Mutated 5' bulgedementia and parkinsonism linked to AGUgugagu Non-mutated 5' bulge 10chromosome 17, Progressive AGUgugaguac 26 Non-mutated 5' bilge 10supranuclear palsy (PSP), AAGguuagug 21 Non-mutated 5'ss  1Corticobasal degeneration (CBD), AAGgugggcc 20 Non-mutated 5' ss  2Argyrophilic grain disease, Pick's CAGgugaggg 42 Non-mutated 5' ss  3disease AAGgussgcg 10 Non-mutated 5' bulge  5 MET Cancer AAGguauauu 15Non-mutated 5' ss 14 MLH1 Colorectal cancer: non-polyposis CGGguaau-2A>G  6 Mutated 5' bulge CAAguaau -1G>A 18 Mutated 5' bulgeHereditary nonpolyposis colorectal CAGgugcag IVS6 + 3A>G  6cancer; Colorectal cancer: non- Mutated 5' bulge polyposisHereditary nonpolyposis colorectal CAGgugcag IVS18 + 3A>G 18 cancerCAGguauag Non-mutated 5' bulge  4 CAGguacag Non-mutated 5' bulge  6CAGguaaugu 34 Non-mutated 5' bulge 10 CAGguacag Non-mutated 5' bulge 18MSH2 Lynch syndrome AAGguaaca Non-mutated 5' bulge  7 CAGguuugcNon-mutated 5' bulge 10 MST1R Cancer, Breast cancer, Colon cancerCAGguaggc Mutated 5' bulge 11 MTHFR Severe deficiency of MTHFR CAGaugaggIVS4 + 1G>A  4 MUT Methylmalonic acidemia AAGguauac Non-mutated 5' bulge 3 AAGguguua ISV8 + 3A>G  8 GAGguaauau 55 Non-mutated 5' bulge 10 MVKMevalonic aciduria CAGguaucc Non-mutated 5' bulge  4 NF1Neurofibromatosis, UAGguguau IVS11 + 3A>G 11 Neurofibromatosis type 1Mutated 5' bulge GGGguaacu IVS3 + 5G>C  3 Neurofibromatosis, CGGguguauIVS7 + 5G>A  7 Neurofibromatosis type I, Neurofibromatosis type IINeurofibromatosis, UAGguauau Non-mutated 5' bulge 15Neurofibromatosis type 1 CAGguaaag Non-mutated 5' bulge 21 GAGguaagaIVS27b del[+1:+10] 27b AAAauaagu IVS28 + 1G>A 28 NeurofibromatosisUAGguaaag Non-mutated 5' bulge 34 CAAGguaccu c.6724 - 4C>U 36 AAGgugccu28 IVS36 + 3A>G 36 NF2 Neurofibromatosis, GAGgugagg IVS12 del[-14:+2] 12Neurofibromatosis type II GAGaugagg IVS12 + 1G>A 12 NR1H4Nonalcoholic steatohepatitis (NASH) CAAguaagua 29 Non-mutated 5' ss  1OAT OAT deficiency CAGguuguc Non-mutated 5' bulge  5 OPA1Autosomal dominant optic atrophy CGGguauau IVS8 + 5G>A  8 OTCOrnithine transcarbamylase deficiency GAGgugugc IVS7 + 3A>G  7 OXTPain, endometritis, Chorioamnionitis  AAGgugaguc 19 Non-mutated 5' ss  1PAH Phenylketonuria CAGguguga IVS5 + 3A>G  5 AGAguaaguNon-mutated 5' bulge  6 CAGguguga IVS10 + 3A>G 10 GAGgugcggg 58Non-mutated 5' ss  1 PBGD Acute intermittent porphyria GCGaugaguIVS1 + 1G>A  1 GCGgagagu IVS1 + 2U>A  1 GCGgugacu IVS1 + 5G>C  1GCGguuagu IVS1 + 3G>U  1 CAUguaggg IVS10 - 1G>U 10 PCCAPropionic acidemia GGUguaagu Non-mutated 5' bulge 14 AAGguauggNon-mutated 5' bulge 18 PDH1 Pyruvate dehydrogenase deficiency AAGguacagNon-mutated 5' bulge 11 PGK1 Pyruvate dehydrogenase deficiency AAGuuaggaIVS4 + 1G>U  4 PHEX X-linked hypophosphatemic rickets AGAgugaguNon-mutated 5' bulge  4 AGAgugagu Non-mutated 5' bulge 14 PKD2Polycystic kidney disease AGUguaagu Non-mutated 5' bulge 13 PKLRPyruvate kinase deficiency CAGgucugga 40 Non-mutated 5' bulge  7GCGguggga IVS9 + 3A>G  9 PKM1 Cancer Cancer metabolism CUGgugaguuc 49Non-mutated 5' ss  9 PKM2 Cancer, Cancer metabolism CAGguaggagg 37Non-mutated 5' bulge 10 PLEKHM1 Autosomal recessive osteopetrosisAGAgugagu Non-mutated 5' bulge  4 type 6 PLKR Lymphoblastic leukemiaAGUgugagu Non-mutated 5' bulge 25 POMT2 Limb-girdle muscular dystrophyGGAguaagg Non-mutated 5' bulge  3 CAGguaaugu 34 Non-mutated 5' bulge 10AGAguaagu Non-mutated 5' bulge 11 AGUgugagu Non-mutated 5' bulge 14PRDM1 B-cell lymphoma CAGgugcgc Non-mutated 5' bulge  6 PRKAR1ACarney complex. GAGgugaag IVS8 + 3A>G  8 PROC Protein C deficiencyACAgugagg IVS3 + 3A>G  3 PSEN1 Alzheimer's disease CAGguacagNon-mutated 5' bulge  3 PTCH1 Basal cell carcinoma GAGguguguNon-mutated 5' bulge  1 PTEN Cowden syndrome GAGgcaggu IVS4 + 2U>C  4AAGauuugu IVS7 + 1U>A  7 PYGM Myophosphorylase deficiency ACCaugaguIVS14 + 1G>A 14 (McArdle disease) RP6KA3 Coffin Lowry Syndrome GAGguguauIVS6 + 3A>G  6 RPGR Retinitis pigmentosa CAGgugua +3A>G  4Mutated 5' bulge AAGguuugg Non-mutated 5' bulge  3 CAGguauagNon-mutated 5' bulge  4 CAGguguag IVS4 + 3A>G  4X-linked retinitis pigmentosa (RP3) CUGuugaga IVS5 + 1G>U  5Retinitis pigmentosa AGGgugcaa IVS10 + 3A>G 10 RSK2Coffin Lowry Syndrome GAGguauau IVS6 + 3A>G  6 SBCAD SBCAD deficiencyGGGguacau IVS3 + 3A>G  3 SCNA Alpha-synuclein, Parkinson's disease, UAGguaggu Non-mutated 5' ss  2 Dementia with Lewy bodies (DLB) CAGguaagcNon-mutated 5 'bulge  3 GAGguagga Non-mutated 5' bulge  5 SCN5ACardiomyopathies GGCguaagu Non-mutated 5' bulge  4 CAGguguguNon-mutated 5' bulge  8 SERPINA1 Emphysema AAGuuaagg IVS2 + 1G>U  2SH2D1A Lymphoproliferative syndrome: X- GAUguaua -1G>U  2 linkedMutated 5' bulge SLC12A3 Gitelman syndrome GGCguaaguNon-mutated 5' bulge 22 SLC6A8 X-linked mental retardation GGAgugaguNon-mutated 5' bulge  3 ACGguagcu IVS10 + 5G>C 10 SMN2Spinal muscular atrophy GGAguaagu IVS7 + 6C>U  7Mutation inducing loss   of U1snRNA affinity SOD1 Familial ALSAAGgcaaggg 5 Non-mutated 5' ss  1 GUGguaagu Non-mutated 5' s  4 SPINK5Netherton syndrome CAGguaau IVS2 + 5G>A  2 AAGguaguaNon-mutated 5' bulge 20 SPTA1 Hereditary blood disorders, AAGguauauNon-mutated 5' bulge  3 Elliptocytosis-2, PyropoikilocytosisSpherocytosis type 3 Hereditary blood disorders, CAGguagagNon-mutated 5' bulge 27 Elliptocytosis-2, Pyropoikilocytosis,  UAGguaugaNon-mutated 5' bulge 41 TMPRSS6 Beta-thalassemia, Iron toxicityAAGgcaggga 6 Non-mutated 5' ss  1 TP53 Cancers GAGgucuggu 57Non-mutated 5' bulge  5 Colorectal tumors AUGgugacc IVS5 + 5G>C  5Squamous cell carcinoma GAAgucugg IVS6 - 1G>A  6 GAGaucugg IVS6 + 1G>A 6 TRAPPC2 Spondyloepiphyseal dysplasia tarda AAGguacgg +4U>C  5Mutated 5' bulge AAGguaugg Non-mutated 5' bulge  4 TSC1Tuberous sclerosis AUGguaaaa Non-mutated 5' bulge  9 AAGguaaugua 13Non-mutated 5' bulge 14 AGAgugaau +5G>A  2 Mutated 5' bulge TSC2Familial tuberous sclerosis AAGgaugag IVS37 + 2 ins[A] 37 TSHBThyroid stimulating hormone. CGGguauau IVS2 + 5G>A  2 TTNDilated cardiomyopathy CAGgugagc Non-mutated 5' ss  1 TTRTTR amyloidosis ACGgugagug 23 Non-mutated 5' ss  1 UBE3ADup15q, Angelman's CAGgucagug 39 Non-mutated 5' ss  1 UGT1A1Crigler-Najjar syndrome type 1 CAGcugugu IVS1 + 1G>C  1 USH2AUsher syndrome type IIa CAGguauug Non-mutated 5' bulge 19 CAGguaaugu 34Non-mutated 5' bulge 28 AAGguaaag Non-mutated 5' bulge 31 GGAguaaguNon-mutated 5' bulge 34 AGAgugagc Non-mutated 5' bulge 39 AUGguauguNon-mutated 5' bulge 70

TABLE 2B  Exemplary targets Mutated  Authentic  Authentic Splice Splice Site Site Cryptic Splice Site Gene Disease Sequence Mutation Exonsequence (Location) HBB Beta-thalassemia CACguuggu IVS1 - 1G>C  1GUGgugagg (IVS1 -16) CAGguuggc IVS1 + 6U>C  1 AUGguuaag (IVS2 +48)CAGauuggu IVS1 + 1G>A  1 AAGgugaac (IVS1 -38) CAGuuuggu IVS1 + 1G>U  1AAGgugaag (Exon2 -135) CAGgcuggu IVS1 + 2U>C  1 CAGguugau IVS1 + 5G>A  1CAGguugcu IVS1 + 5G>C  1 CAGguuguu IVS1 + 5G>U  1 AGGgugucuIVS2 del[+4:+5]  2 PBGD Acute GCGaugagu     IVS1 + 1G>A  1CGGgugggg (Exon 10 -9) intermittent CAUguaggg IVS10 - 1G>U 10 porphyriaGCGgagagu IVS1 + 2U>A  1 GCGgugacu IVS1 + 5G>C  1 GCGguuagu IVS1 + 3G>U 1 HBA2 Alpha- GAGgcuccc IVS1 del[+2:+6]  1 GGGguaagg (Exonl -49)thalassemia AR Androgen CUGuuaag IVS4 + 1G>U  4 Sensitivity ATM Ataxia-CAGauaacu IVS45 + 1G>A 45 AGAgugacu(IVS45 +72) telangiectasia BRCA1Breast Cancer UUUgugagc IVS16 + 6U>C 16 UAUguaaga(Exon5 -22) AGGguauauIVS5 - 2A>G  5 UAGguauug(IVS16 +70) CYP27A1 Cerebrotendinous GAGguaggaIVS6 - 2C>A  6 GUGgugggu (Exon6 -89) xanthomatosis GCAguagga IVS6 - 1G>A 6 FAH Chronic CCGgugaau IVS12 + 5G>A 12 GAGgugggu (IVS112 +106)Tyrosinemia Type 1 TP53 Colorectal tumors AUGgugacc IVS5 + 5G>C FGACommon GAGuuaagu IVS4 + 1G>U  4 GGAguuaag(Exon4 -66) congenitalUAAguauua(Exon4 -36) afibrinogenemia PTEN Cowden AAGauuugu IVS7 + 1G>A 7 CAUguaagg(IVS7 +76) syndrome GAGgcaggu IVS4 + 2U>C  4 UGT1A1Crigler-Najjar CAGcugugu IVS1 + 1G>C  1 GAGgugacu(Exon1 -141)syndrome type 1 CFTR Cystic Fibrosis CACgugagc IVS20 - 1G>C 20AUUgugagg (Exon4 -93) AAGuuaaua IVS4 + 1G>U  4 COL7A1 Dominant AGGgugaggExon73 del[-98:-71] CUGguauuc(Exon73 -62) Dystrophic epidermolysisbullosa KRT5 Dowling-Meara AAGaugagc IVS1 + 1G>A  1 AGGgugagg(Exonl -66)epidermolysis bullosa simplex DMD Duchenne and GCUguaacu IVS64 + 5G>C 64AAGggaaaa (IVS26+2U>G) Becker muscular dystrophy COL3A1 Ehlers-DanlosGAUaugagu IVS42 + 1G>A 42 GGAguaagc(IVS16 +24) syndrome IV CCUauaaguIVS16 + 1G>A 16 CGCauaagu IVS20 + 1G>A 20 LPL  Familial ACGauaaggIVS2 + 1G>A  2 CAGguggga(IVS2 +143) hypercholesteroleGAGguuggu(IVS2 +247) mia AGAgugagg(IVS2 +383) LDLR  Familial GAGgcguggIVS12 + 2U>C 12 UACguacga(IVS12 +12) hypercholesterole mia TSC2Familial tuberous AAGgaugag IVS37 + 2 ins[A] 37 CCGgugagg(Exon37 -29)sclerosis F7 FVII deficiency UGGgugggug IVS7 + 7A>G  7UGGgugggu (IVS7 +38) UGGguggau IVS7 + 5G>A  7 UGGguacca IVS7del[+3:+6] 7 ITGB3 Glanzmann GAUaugagu IVS4 + 1G>A  4 CAGgugugg (IVS4 +28)thrombasthenia C3 Hereditary C3 UGGauaagg IVS18 + 1G>A 18GAAgugagu (Exon18 -61) deficiency HMGCL Hereditary HL ACGcuaagcIVS7 + 1G>C  7 GGGguauuu (IVS7 +79) deficiency APOB Homozygous AAGgcaaaaIVS24 + 2U>C 24 hypobetalipoprot einemia LMNA Hutchinson- CAAgugaguIVS11 - 1G>A 11 CAGgugggc(Exon 11) Gilford progeria CAGgugacuIVS11 + 5G>C 11 syndrome CAGaugagu IVS11 + 1G>A 11 (HGPS) CAGgcgaguIVS11 + 2U>C 11 HPRT1 Lesch-Nyhan GAAggaagu IVS5 + 2U>G  5AAGguaagc (IVS5 +68) syndrome GAAgugugu IVS5 + 3:4AA>GU  5 GAAguaaauIVS5 + 5G>A  5 GAAuaaguu IVS5del[G1]  5 ITGB2 Leukocyte UUCauaaguIVS7 + 1G>A  7 AGGgugggg (IVS7 +65) adhesion deficiency FBN1Marfan syndrome UAGaugcgu IVS46 + 1G>A 46 GAAgucagu (IVS46 +34) GCKMaturity onset CCUgugagg(Exon4 -24) diabetes of the young (MODY) COL6A1Mild Bethlem GGGaugagu IVS3 + 1G>A  3 CAAguacuu(Exon3 -66) myopathy IDSMucopolysacchar AUUuuaagc IVS7-1:+1GG>UU  7 CUGgugagu (IVS7 +23)idosis type II (Hunter syndrome) GHV Mutation in UUUauaagc IVS2 + 1G>A 2 UGGguaaug (IVS2 +13) placenta YGM Myophosphorylase ACCaugaguIVS14 + 1G>A 14  CAGgugaag (Exon14 -67) deficiency (McArdle disease) NF1Neurofibromatosis AAAauaagu IVS28 + 1G>A 28 AACguuaag (Exon27b -69)type I GAGguaaga IVS27b del[+1:+10] 27b AAGguauuc(Exon28 -4) NF2Neurofibromatosis GAGgugagg IVS12 del[-14:+2] 12 GAUguacgg(Exon7 -23)type II GAGaugagg IVS12 + 1G>A 12 AAGgugcug (Exon12 -38) CGGguguauIVS7 + 5G>A  7 GAGgugcug(Exon12 -53) ACGguguga(Exon7 -28) PGK1Phosphoglycerate AAGuuagga IVS4 + 1G>U  4 GGGgugagg (IVS4 +31)kinase deficiency CYP19 Placental UGUgcaagu IVS6 + 2U>C  6 aromatasedeficiency PKD1 Polycystic kidney CAGguggcg(Exon43 -66) disease 1 COL7A1Recessive GUAgugagu IVS95 - 1G>A 95 GGGgucagu (Exon95 -7) dystrophicAGGgugauc IVS3 - 2A>G  3 UCCgugagc (Exon 3 -104) epidermolysis bullosaRisk for AAGuuaagg IVS2 + 1G>U  2 AGGguacuc (Exon2 -84) emphysemaSandhoff disease UUGguaaca IVS8 + 5G>C  8 AAUguuggu(Exon8 -4) MTHFRSevere deficiency CAGaugagg IVS4 + 1G>A  4 of MTHFR F5 Severe factor VCAUguauuu IVS10 - 1G>U 10 UCUguaaga (Exon10 -35) deficiency COL1A1Severe type III CCUaugagu IVS8 + 1G>A  8 UUGguaaga osteogenesisCCUgugaau IVS8 + 5G>A (IVS8 G +97; exon 8 ±26) imperfectaCUGgugagc (IVS8 +97) CUGgugaca (Exon34 -8) HPRT1 Somatic GUGgugagcIVS1del[-2:+34]  1 CAGguggcg (IVS1 +50) mutations in GUGgugauc  1kidney tubular epithelial cells TP53 Squamous cell GAAgucugg IVS6 - 1G>A 6 carcinoma GAGaucugg IVS6 + 1G>A  6 HXA Tay-Sachs GACaugaggIVS9 + 1G>A  9 AGGgugggu (IVS9 +18) Syndrome ABCD1 X-linked GAAgugggIVS1 - 1G>A  1 CAGguuggg (IVS1 +10) adrenoleukodystr ophy (X-ALD) RPGRX-linked retinitis CUGuugaga IVS5 + 1G>U  5 CAUguaauu (Exon5 -76)pigmentosa (RP3)

^(A) TABLE 2C Exemplary targets with AGAguaag splice site sequenceGenomic Genomic Genomic Genomic Gene Chr Location Location Strand GeneChr Location Location Strand EPHA3 3 89604444 89604474 + UNC5C 496382587 96382617 − PCOTH 13 23361677 23361707 + DNAH8 6 3906004639060076 + NDFIP2 13 79005577 79005607 + POMT2 14 76824842 76824872 −FZD6 8 104409805 104409835 + MAGT1 X 76983383 76983413 − PTPN3 9111222509 111222539 − HSPA9 5 137921441 137921471 − AFP 4 7453719074537220 + PTPRK 6 128339479 128339509 − CBX3 7 26212640 26212670 + RP18 55697386 55697416 + PHACTR4 1 28675375 28675405 + PTPN4 2 120434984120435014 + TAF2 8 120826286 120826316 − C19orf42 19 16627033 16627063 −KCNT2 1 194552885 194552915 − TG 8 133982965 133982995 + PRIM1 1255431073 55431103 − PIGT 20 43481629 43481659 + CDH9 5 26941809 26941839− CDC42BPB 14 102495705 102495735 − SLC38A1 12 44883044 44883074 −TOM1L1 17 50382471 50382501 + HDX X 83643077 83643107 − USP39 2 8571674985716779 + RAB23 6 57194060 57194090 − POSTN 13 37058903 37058933 − STX311 59312981 59313011 + PAH 12 101773028 101773058 − DNAH3 16 2105306521053095 − ARHGEF2 1 154191301 154191331 − SSX3 X 48100997 48101027 −RBM39 20 33773060 33773090 − NSMAF 8 59670657 59670687 − C21orf70 2145204496 45204526 + XRN2 20 21283495 21283525 + GAS2L3 12 9954027699540306 + EVC2 4 5715719 5715749 − UXT X 47401510 47401540 − ERCC8 560223605 60223635 − C16orf48 16 66257459 66257489 − QRSL1 6 107210285107210315 + CMIP 16 80282931 80282961 + CEP110 9 122943672 122943702 +CA11 19 53834602 53834632 − FANCA 16 88404822 88404852 − PHKB 1646251964 46251994 + DYNC1H1 14 101544412 101544442 + ADAMTS9 3 6460254864602578 − TRIML1 4 189298099 189298129 + SETD3 14 99001777 99001807 −MKL2 16 14213752 14213782 + DENND2D 1 111532831 111532861 − CHAF1A 194369058 4369088 + GAB1 4 144600066 144600096 + CCDC11 18 4603111046031140 − COL4A2 13 109888370 109888400 + ALS2CL 3 46704576 46704606 −PADI4 1 17555526 17555556 + C13orf1 13 49390214 49390244 − MYOM3 124260121 24260151 − JAK1 1 65079706 65079736 − ARPC3 12 109367624109367654 − PAN2 12 54998272 54998302 − TBC1D3G 17 31873637 31873667 −PRKG1 10 52897587 52897617 + USP6 17 4981754 4981784 + KREMEN1 2227824926 27824956 + COG3 13 44958696 44958726 + ADAMTS9 3 6461171764611747 − ATP6V1G3 1 196776306 196776336 − PDS5B 13 32228079 32228109 +KIR2DL5B 19 237531 237561 + PTPRM 18 8374669 8374699 + KIR3DL2 1960069161 60069191 + DPP4 2 162570485 162570515 − KIR3DL3 19 5993862159938651 + L3MBTL2 22 39955591 39955621 + HTT 4 3186721 3186751 + EFCAB317 57837751 57837781 + CEP192 18 13086291 13086321 + GRHPR 9 3741281537412845 + TEAD1 11 12859159 12859189 + ARHGEF18 19 7434826 7434856 +CD4 12 6775799 6775829 + MLX 17 37977597 37977627 + SUCLG2 3 6766218567662215 − ABCB5 7 20649508 20649538 + VTI1B 14 67192870 67192900 −MAP4K4 2 101814730 101814760 + L3MBTL 20 41598497 41598527 + L1CAM X152786433 152786463 − GCG 2 162710280 162710310 − CLPB 11 7168300171683031 − MCF2L2 3 184428763 184428793 − GNB5 15 50203946 50203976 −MYCBP2 13 76590460 76590490 − TRAF3IP3 1 208021411 208021441 + AP2A2 11971284 971314 + WDR26 1 222673827 222673857 − GRAMD3 5 125829912125829942 + ARHGAP1 11 46675131 46675161 − ATAD5 17 26245279 26245309 +PPP4C 16 30001341 30001371 + PDS5A 4 39540218 39540248 − MRPS35 1227768371 27768401 + GRM3 7 86307142 86307172 + WDR17 4 177254715177254745 + TG 8 134030355 134030385 + CLIC2 X 154162429 154162459 −SPAG9 17 46430788 46430818 − ARS2 7 100323401 100323431 + PLEKHA7 1116849206 16849236 − MYO3A 10 26483743 26483773 + KATNAL2 18 4284000842840038 + EPS15 1 51701917 51701947 − COL5A2 2 189629928 189629958 −ANK3 10 61570100 61570130 − ERN2 16 23629322 23629352 − CNOT1 1657148251 57148281 − TFRC 3 197264670 197264700 − FBXO38 5 147770506147770536 + TET2 4 106384369 106384399 + PLXNC1 12 93142207 93142237 +KRTCAP2 1 153411649 153411679 − DMD X 32392608 32392638 − MEGF10 5126802143 126802173 + TMEM27 X 15587044 15587074 − IWS1 2 127977417127977447 − CDH10 5 24570962 24570992 − COL2A1 12 46656548 46656578 −GOLT1B 12 21546134 21546164 + FAM20A 17 64062497 64062527 − NUMA1 1171412952 71412982 − PDIA3 15 41842681 41842711 + IMMT 2 8622668686226716 − CDC2L5 7 40084960 40084990 + SSX9 X 48050476 48050506 −SMARCA1 X 128473446 128473476 − SSX5 X 47941095 47941125 − NFRKB 11129257540 129257570 − PPP1R12A 12 78790703 78790733 − CPXM2 10 125629701125629731 − TBCEL 11 120429636 120429666 + BCS1L 2 219235631 219235661 +MYO9B 19 17167267 17167297 + NFIX 19 13045295 13045325 + PRPF40B 1248316028 48316058 + SPECC1L 22 23050380 23050410 + C10orf137 10127414448 127414478 + NAG 2 15350096 15350126 − PDK4 7 95060931 95060961− KIF16B 20 16426242 16426272 − MEGF11 15 63995524 63995554 − AKAP3 124621310 4621340 − FLJ35848 17 40102396 40102426 + PROX1 1 212228672212228702 + SLC13A1 7 122556119 122556149 − MATN2 8 99102716 99102746 +MADD 11 47270708 47270738 + STAMBPL1 10 90663180 90663210 + ADAM10 1556723361 56723391 − EPHB1 3 136451008 136451038 + MYH2 17 1038055610380586 − TTPAL 20 42548745 42548775 + IL5RA 3 3121571 3121601 − PVRL219 50077446 50077476 + RLN3 19 14002153 14002183 + ZNF618 9 115837321115837351 + CCDC81 11 85803988 85804018 + COL4A5 X 107710609 107710639 +SENP3 17 7408890 7408920 + FAM13C1 10 60792149 60792179 − ACSS2 2032977730 32977760 + VPS35 16 45272068 45272098 − TRIM65 17 7139947371399503 − SPP2 2 234624463 234624493 + LOC390110 11 44028232 44028262 +FAM19A1 3 68670706 68670736 + SENP6 6 76388046 76388076 + NRXN1 250576531 50576561 − PIK3C2G 12 18607684 18607714 + HIPK3 11 3332692533326955 + SLC38A4 12 45458323 45458353 − CAPN9 1 228992543 228992573 +HDAC5 17 39526192 39526222 − CEP170 1 241406611 241406641 − MGAM 7141380633 141380663 + FGFR1OP 6 167358357 167358387 + YARS 1 3302057633020606 − ADCY8 8 131917689 131917719 − C1R 12 7132560 7132590 − MAGI13 65403491 65403521 − TIMM50 19 44670682 44670712 + UNC45B 17 3050585830505888 + SEC24A 5 134038791 134038821 + C16orf33 16 46598 46628 +NOS2A 17 23138815 23138845 − GRN 17 39783979 39784009 + FBXO18 106003311 6003341 + KIF9 3 47293760 47293790 − PKHD1L1 8 110482978110483008 + LMO2 11 33847452 33847482 − GSDMB 17 35315874 35315904 −C13orf15 13 40930591 40930621 + C8orf33 8 146249321 146249351 + FNBP1L 193771198 93771228 + PROCR 20 33222668 33222698 + CCDC102B 18 6465712864657158 + FEZ2 2 36661921 36661951 − C15orf29 15 32226677 32226707 −KIAA1033 12 104025754 104025784 + ARHGAP18 6 129970715 129970745 − FANK110 127575199 127575229 + C9orf98 9 134692499 134692529 − COMTD1 1076664358 76664388 − GRIA3 X 122389656 122389686 + REC8 14 2371641423716444 + DNAI1 9 34473463 34473493 + ATG4A X 107267755 107267785 +PIWIL3 22 23475355 23475385 − GTPBP4 10 1045505 1045535 + SLC4A2 7150394766 150394796 + PLCG1 20 39234328 39234358 + CRKRS 17 3492985134929881 + CDH24 14 22593539 22593569 − OBFC2B 12 54905731 54905761 +PRRG2 19 54783686 54783716 + C14orf118 14 75712771 75712801 + KIF5A 1256256413 56256443 + DCTN3 9 34608657 34608687 − C1orf130 1 2479457524794605 + COL4A1 13 109656997 109657027 − ARFGEF2 20 4703859147038621 + CDCA8 1 37938765 37938795 + NME7 1 167534402 167534432 −PARVB 22 42863716 42863746 + SEL1L 14 81022370 81022400 − FGFR1OP2 1226982895 26982925 + MME 3 156369265 156369295 + STXBP1 9 129414525129414555 + PRIM2 6 57293302 57293332 + BMPR2 2 203129484 203129514 +DNAJC13 3 133724516 133724546 + SNRP70 19 54293758 54293788 + PPP4R1L 2056246657 56246687 − ACADL 2 210793600 210793630 − LUM 12 9002601090026040 − TBC1D8B X 105950866 105950896 + ZNF37A 10 38424723 38424753 +MUC2 11 1073587 1073617 + SNRK 3 43348791 43348821 + POMT2 14 7682331376823343 − SPAG9 17 46511928 46511958 − CAPSL 5 35946209 35946239 − JAK29 5063770 5063800 + BRSK2 11 1429210 1429240 + C1orf114 1 167654859167654889 − ERGIC3 20 33605556 33605586 + CSE1L 20 47140951 47140981 +DDA1 19 17286183 17286213 + MRPS28 8 81077773 81077803 − CDK8 1325872672 25872702 + NSMCE2 8 126183896 126183926 + TP63 3 191068410191068440 + NUBPL 14 31138321 31138351 + INPP5D 2 233757891 233757921 +C5orf34 5 43544988 43545018 − MAPK8IP3 16 1714664 1714694 + MRPL39 2125886979 25887009 − TNFRSF8 1 12108681 12108711 + MTF2 1 9335374893353778 + AMBRA1 11 46396023 46396053 − FANCM 14 44720643 44720673 + F31 94774093 94774123 − EPB41L5 2 120601882 120601912 + HSPG2 1 2205924122059271 − ADAMTS20 12 42146706 42146736 − RHPN2 19 38209234 38209264 −RFC4 3 187995125 187995155 − RP11-265F1 1 15682467 15682497 + PIAS1 1566226077 66226107 + ELA2A 1 15662589 15662619 + CUL5 11 107465545107465575 + GRM4 6 34115917 34115947 − COL5A2 2 189615675 189615705 −GOLT1A 1 202449617 202449647 − FN1 2 215951127 215951157 − LGMN 1492254829 92254859 − PROSC 8 37749550 37749580 + TNK2 3 197080749197080779 − LHX6 9 124015690 124015720 − LRP4 11 46867522 46867552 −SCYL3 1 168114383 168114413 − SEC24A 5 134041726 134041756 + MALT1 1854518788 54518818 + EFCAB4B 12 3658326 3658356 − C15orf42 15 8794490587944935 + MAPK9 5 179621274 179621304 − DIP2A 21 46773509 46773539 +SH3RF2 5 145415954 145415984 + WDR44 X 117454800 117454830 + NKAP X118956705 118956735 − KIN 10 7865034 7865064 − CALCOCO2 17 4427423344274263 + FGFR2 10 123313990 123314020 − DDX1 2 15677956 15677986 +OSBPL8 12 75287532 75287562 − PRMT7 16 66912851 66912881 + TCEB3 123956187 23956217 + TDRD3 13 59939499 59939529 + MYO19 17 3192901631929046 − PPFIA2 12 80375659 80375689 − APOB 2 21104688 21104718 −COL24A1 1 86021751 86021781 − RP13-36C9. X 134715052 134715082 +STAMBPL1 10 90671117 90671147 + RP13-36C9. X 134777728 134777758 − KIF153 44865039 44865069 + CT45-6 X 134794978 134795008 − ANXA11 10 8190609881906128 − XX-FW88277 X 134680521 134680551 + PIK3C2G 12 1841549718415527 + CEP110 9 122959964 122959994 + COL29A1 3 131625419131625449 + SPATS1 6 44428573 44428603 + ERMN 2 157892215 157892245 −C9orf114 9 130631194 130631224 − GNAS 20 56904119 56904149 + STK17B 2196712573 196712603 − SULF2 20 45734333 45734363 − CCDC18 1 9345599993456029 + TRPM7 15 48654325 48654355 − NCOA1 2 24803064 24803094 +ALAS1 3 52208481 52208511 + TTLL5 14 75199304 75199334 + COPZ2 1743466212 43466242 − SH3PXD2A 10 105474002 105474032 − OLIG2 21 3332018933320219 + DOCK4 7 111192394 111192424 − FAM13A1 4 89889929 89889959 −MTDH 8 98804424 98804454 + RPN1 3 129823681 129823711 − COL24A1 186145449 86145479 − SRP72 4 57028652 57028682 + ADAMTS6 5 6463155264631582 − LPCAT2 16 54137215 54137245 + SENP7 3 102529996 102530026 −SGCE 7 94066929 94066959 − PIGN 18 57928031 57928061 − C1orf107 1208070996 208071026 + TOP2B 3 25623650 25623680 − UTP18 17 4669862546698655 + NUPL1 13 24787590 24787620 + UVRAG 11 75405657 75405687 +OSBPL11 3 126761897 126761927 − PRC1 15 89318803 89318833 − CCDC5 1841954009 41954039 + CUBN 10 17125816 17125846 − COPS7B 2 232364112232364142 + NEK5 13 51574054 51574084 − POLN 4 2200608 2200638 − EPHB3 3185781875 185781905 + VTI1A 10 114418022 114418052 + ZNF114 19 5346688253466912 + SYTL5 X 37833769 37833799 + CAMK1D 10 12906542 12906572 +CETP 16 55561399 55561429 + NOTCH1 9 138517439 138517469 − LMLN 3199185727 199185757 + ADAL 15 41415301 41415331 + C11orf70 11 101442577101442607 + SPATA13 13 23758516 23758546 + LMBRD2 5 36145788 36145818 −CAMKK1 17 3740720 3740750 − DNTTIP2 1 94111247 94111277 − C9orf86 9138837917 138837947 + ECM2 9 94304600 94304630 − FRAS1 4 7951302179513051 + PRKG1 10 53563656 53563686 + CENTG2 2 236614209 236614239 +C16orf38 16 1477302 1477332 − PTPRD 9 8330327 8330357 − RBM45 2178696609 178696639 + UHRF1BP1 6 34910601 34910631 + C1orf94 1 3441628234416312 + JAK1 1 65084904 65084934 − GRIA1 5 152869544 152869574 + LYST1 233985385 233985415 − HDAC3 5 140988294 140988324 − CPSF2 14 9169732891697358 + IPO4 14 23727246 23727276 − PUS10 2 61041015 61041045 − MYOM28 2077714 2077744 + COL1A2 7 93882503 93882533 + NARG1 4 140501217140501247 + DPP4 2 162587495 162587525 − HEPACAM2 7 92659487 92659517 −SEC24D 4 119905389 119905419 − SDK2 17 68955333 68955363 − ADCY10 1166139733 166139763 − FBXO15 18 69958923 69958953 − CDH8 16 6062746960627499 − SNX6 14 34120502 34120532 − ZC3HAV1 7 138396306 138396336 −BBOX1 11 27097953 27097983 + SKAP1 17 43620188 43620218 − C3orf23 344417815 44417845 + FAM23B 10 18105150 18105180 + ETS2 21 3910817139108201 + RTEL1 20 61779965 61779995 + CDC16 13 114040792 114040822 +ZNF365 10 63806686 63806716 + CFH 1 194908901 194908931 + SAE1 1952348122 52348152 + ANTXR2 4 81171785 81171815 − STARD6 18 5010969950109729 − PIK3CG 7 106300268 106300298 + TBK1 12 63170151 63170181 +EDEM3 1 182968578 182968608 − SETD4 21 36335959 36335989 − IL1R2 2102002691 102002721 + ZWINT 10 57790947 57790977 − KPNA5 6 117133001117133031 + GRIN2B 12 13611210 13611240 − LHCGR 2 48779242 48779272 −TNFRSF10A 8 23110574 23110604 − NOL10 2 10720520 10720550 − TNFRSF10B 822937630 22937660 − CYP3A4 7 99205311 99205341 − ROCK2 2 1125181711251847 − TTC17 11 43369687 43369717 + ABCA9 17 64568586 64568616 −FAR2 12 29366109 29366139 + GRIA4 11 105302860 105302890 + COL3A1 2189563316 189563346 + EXO1 1 240082321 240082351 + ZBTB20 3 115826398115826428 − PRAME 22 21231362 21231392 − COL19A1 6 70907587 70907617 +C8B 1 57170055 57170085 − NUP160 11 47797486 47797516 − PAPOLG 260867690 60867720 + SCO1 17 10539767 10539797 − CDH8 16 6041640160416431 − VWA3B 2 98283096 98283126 + KIAA0586 14 58025330 58025360 +COL3A1 2 189580894 189580924 + GSTCD 4 106907867 106907897 + CYP3A43 799283798 99283828 + STAG1 3 137635072 137635102 − DHRS7 14 5969041459690444 − CLINT1 5 157148933 157148963 − MIB1 18 17687162 17687192 +KCNN2 5 113836745 113836775 + NLRC5 16 55670690 55670720 + GART 2133800135 33800165 − POLR3D 8 22160707 22160737 + DDX24 14 9359618193596211 − ATP11C X 138696982 138697012 − AKAP10 17 19785715 19785745 −ADAM15 1 153296186 153296216 + LRPPRC 2 43980093 43980123 − FAM65C 2048645297 48645327 − DOCK11 X 117654388 117654418 + SCN3A 2 165733476165733506 − LAMA2 6 129506903 129506933 + CYP3A5 7 99102144 99102174 −HNRNPH1 5 178975689 178975719 − COL1A1 17 45624324 45624354 − RAB11FIP210 119795296 119795326 − FGR 1 27820641 27820671 − COL9A1 6 7103672271036752 − MIER2 19 276619 276649 − LRRC42 1 54186227 54186257 + SIPA1L319 43283691 43283721 + KRIT1 7 91693760 91693790 − CDH11 16 6358315663583186 − PLEKHA5 12 19299351 19299381 + SYCP1 1 115203939 115203969 +MLANA 9 5882536 5882566 + ASH1L 1 153652143 153652173 − CCDC15 11124334355 124334385 + FAM13B1 5 137351846 137351876 − CACNA2D1 781437911 81437941 − COL4A5 X 107693797 107693827 + SCN1A 2 166621151166621181 − PRPF4B 6 3966684 3966714 + SENP6 6 76480002 76480032 +PTPN11 12 111424428 111424458 + DNAJA4 15 76345675 76345705 + LAMB1 7107367654 107367684 − AP4E1 15 49063619 49063649 + PIK3R1 5 6762705767627087 + LAMB1 7 107413687 107413717 − FLNA X 153243216 153243246 −TCP11L2 12 105254106 105254136 + SKIV2L2 5 54698445 54698475 + GOLGB1 3122884438 122884468 − RNFT1 17 55394667 55394697 − C20orf74 20 2051349320513523 − PDCD4 10 112644255 112644285 + WDFY2 13 51228584 51228614 +AHCTF1 1 245137460 245137490 − MGC34774 7 77817519 77817549 + DHFR 579965436 79965466 − DNAJC7 17 37394932 37394962 − UTP15 5 7289989372899923 + RPAP3 12 46347014 46347044 − TMEM156 4 38666850 38666880 −PTK2B 8 27343574 27343604 + TNKS 8 9604951 9604981 + RNF32 7 156128527156128557 + NFIA 1 61570831 61570861 + COL22A1 8 139862336 139862366 −NT5C3 7 33021791 33021821 − VAPA 18 9940550 9940580 + TNKS2 10 9358073693580766 + MGAT4A 2 98641097 98641127 − COL11A1 1 103227646 103227676 −RYR3 15 31920361 31920391 + PCNX 14 70583560 70583590 + MYB 6 135552699135552729 + MEMO1 2 31999355 31999385 − SPATA4 4 177351087 177351117 −LMBRD1 6 70467362 70467392 − FZD3 8 28465172 28465202 + NEDD4 1554030850 54030880 − CR1 1 205847289 205847319 + PPP3CB 10 7490121674901246 − C18orf8 18 19360712 19360742 + C1orf71 1 244864497244864527 + CHIC2 4 54609863 54609893 − CAB39 2 231383266 231383296 +TRIML2 4 189255193 189255223 − POMT2 14 76848378 76848408 − WRNIP1 62715579 2715609 + TP53INP1 8 96013458 96013488 − INTU 4 128814803128814833 + CDC14A 1 100706223 100706253 + WDR67 8 124231534 124231564 +KLF3 4 38367880 38367910 + C1orf149 1 37747450 37747480 − NEK1 4170760224 170760254 − ELA1 12 50021279 50021309 − PPP4R2 3 7319288673192916 + C12orf51 12 111115232 111115262 − KLF12 13 73285274 73285304− LIMCH1 4 41335726 41335756 + PHTF1 1 114042391 114042421 − ROCK1 1816793783 16793813 − COL2A1 12 46674028 46674058 − COL4A6 X 107440618107440648 − KIAA1622 14 93792679 93792709 + AGL 1 100153615 100153645 +TTN 2 179343016 179343046 − WWC3 X 10062621 10062651 + PSD3 8 1853438718534417 − GPATCH1 19 38295344 38295374 + LACE1 6 108905173 108905203 +IFI44L 1 78867257 78867287 + SLC28A3 9 86104300 86104330 − NLRC3 163538120 3538150 − COPA 1 158533741 158533771 − DCC 18 4899595048995980 + PAPOLG 2 60849514 60849544 + ARHGEF18 19 7433205 7433235 +CENPI X 100268896 100268926 + MPI 15 72972181 72972211 + ARFGEF1 868328224 68328254 − PTPN22 1 114169271 114169301 − EXOC4 7 133273347133273377 + KIAA1622 14 93744641 93744671 + TIAM2 6 155607594155607624 + DEPDC2 8 69158162 69158192 + MDGA2 14 46384703 46384733 −NARG2 15 58527445 58527475 − BRCC3 X 153972293 153972323 + COL25A1 4109972969 109972999 − MEGF10 5 126804443 126804473 + ENPP3 6 132040758132040788 + WDTC1 1 27481348 27481378 + UTRN 6 144900531 144900561 +EMCN 4 101605587 101605617 − CUBN 10 17022021 17022051 − FUT9 6 9657555596575585 + TIAL1 10 121326097 121326127 − NPM1 5 170752572 170752602 +USP38 4 144346814 144346844 + GPR160 3 171280364 171280394 + SIPA1L2 1230686145 230686175 − OSGEPL1 2 190334602 190334632 − NUPL1 13 2479147324791503 + SGPL1 10 72274386 72274416 + SUPT16H 14 20901216 20901246 −CEP192 18 13028563 13028593 + KIAA1219 20 36608472 36608502 + CHN1 2175491492 175491522 − JAK2 9 5070365 5070395 + FLJ36070 19 5391175853911788 − GALNT3 2 166323487 166323517 − CELSR3 3 48652095 48652125 −ZC3HC1 7 129477503 129477533 − GLT8D1 3 52704461 52704491 − COL1A2 793878387 93878417 + COL14A1 8 121423851 121423881 + CBX1 17 4350921043509240 − SAAL1 11 18074878 18074908 − SMC5 9 72102942 72102972 +SH3TC2 5 148386600 148386630 − ANXA10 4 169342392 169342422 + SEC31A 484014772 84014802 − XRN1 3 143566826 143566856 − LVRN 5 115357435115357465 + CREBBP 16 3734880 3734910 − TLK2 17 57984833 57984863 + NOS112 116186061 116186091 − KIF5B 10 32349940 32349970 − SMARCA5 4144667048 144667078 + EML5 14 88282266 88282296 − VPS29 12 109421707109421737 − TMF1 3 69176317 69176347 − PLD1 3 172935333 172935363 − TMF13 69155880 69155910 − PIGF 2 46694321 46694351 − TRIM44 11 3564188935641919 + C1orf27 1 184621823 184621853 + PTK2 8 141925525 141925555 −TCF12 15 55143298 55143328 + MLL5 7 104468691 104468721 + COL24A1 185999651 85999681 − ABCB1 7 87034021 87034051 − MRAP2 6 8482941584829445 + SGOL2 2 201148414 201148444 + FOLH1 11 49161261 49161291 −PAWR 12 78512224 78512254 − PSMAL 11 89035044 89035074 + NUBP1 1610769375 10769405 + SH3PXD2B 5 171741629 171741659 − PHLDB2 3 113142167113142197 + KIAA0256 15 47088689 47088719 − ISL2 15 74416322 74416352 +C4orf18 4 159271372 159271402 − CNOT7 8 17145306 17145336 − NR4A3 9101635542 101635572 + UTX X 44823525 44823555 + FAM184A 6 119342986119343016 − COL5A2 2 189631804 189631834 − PDE8B 5 76743287 76743317 +DSCC1 8 120925014 120925044 − DDX4 5 55116914 55116944 + RB1CC1 853705567 53705597 − ERN1 17 59511851 59511881 − PLCB4 20 94014799401509 + COL12A1 6 75868020 75868050 − ASPM 1 195328789 195328819 −COPB2 3 140573239 140573269 − ERMP1 9 5801095 5801125 − ICA1 7 81479048147934 − LIMK2 22 29986048 29986078 + NUP98 11 3759832 3759862 − HERC115 61733355 61733385 − GJA1 6 121798662 121798692 + CHD9 16 5185449551854525 + LRRC19 9 26989596 26989626 − THOC2 X 122599559 122599589 −IPO8 12 30709405 30709435 − SCN11A 3 38961890 38961920 − CDK5RAP2 9122255539 122255569 − SLC39A10 2 196281798 196281828 + UTY Y 1394481313944843 − PLCB1 20 8717354 8717384 + EIF3A 10 120806226 120806256 −CXorf41 X 106348840 106348870 + ASNSD1 2 190238407 190238437 + CENTB2 3196547261 196547291 − ^(A) Homo sapiens (human) genome assembly GRCh37(hg19) from Genome Reference Consortium

^(A) TABLE 2D Exemplary SMSM Splice Site Targets with GGAguaag splicesite sequence Genomic Genomic Genomic Genomic Gene Chr location locationStrand Gene Chr location location Strand CD1B 1 156565768 156565798 −C6orf118 6 165614944 165614974 − ZFYVE1 14 72514372 72514402 − PDLIM5 495794799 95794829 + LENG1 19 59352297 59352327 − USP1 1 6268691062686940 + PRUNE2 9 78424060 78424090 − HLTF 3 150250693 150250723 −HLA-DPB1 6 33161542 33161572 + ERBB4 2 211960899 211960929 − GSTO2 10106047417 106047447 + C4orf29 4 129161828 129161858 + BRSK1 19 6050603260506062 + UTP20 12 100293650 100293680 + GAPDH 12 6517578 6517608 +CRYZ 1 74952835 74952865 − TTLL9 20 29950014 29950044 + DCBLD1 6117960234 117960264 + CACHD1 1 64820560 64820590 + KIF3B 20 3037833330378363 + DPP3 11 66019521 66019551 + AKNA 9 116161679 116161709 −LRWD1 7 101892597 101892627 + RALGDS 9 134965460 134965490 − CYFIP2 5156685209 156685239 + TM6SF1 15 81579422 81579452 + KIAA1787 17 71651397165169 − PMFBP1 16 70714298 70714328 − KCNN2 5 113850384 113850414 +TBC1D29 17 25911845 25911875 + SLC25A14 X 129301993 129302023 + FAM161A2 61927382 61927412 − CEL 9 134934051 134934081 + TBC1D26 17 1558703215587062 + TRPM3 9 72443834 72443864 − ZNF169 9 96088900 96088930 +DPY19L2P2 7 102707805 102707835 − KIAA1409 14 93218778 93218808 +COL17A1 10 105787368 105787398 − NFE2L2 2 177807182 177807212 − TRPM5 112383317 2383347 − PRKCA 17 62213539 62213569 + ITGB1 10 3325478933254819 − CLPTM1 19 50172542 50172572 + ACTG2 2 73982100 73982130 +MCM6 2 136350283 136350313 − TECTB 10 114049297 114049327 + TMEM194A 1255750708 55750738 − SYCP2 20 57890379 57890409 − SCN4A 17 5940321259403242 − KIAA1166 X 64056670 64056700 − TUSC3 8 15645477 15645507 +RTF1 15 39549867 39549897 + GBGT1 9 135028946 135028976 − MGAM 7141368693 141368723 + CCDC146 7 76721801 76721831 + PCBP4 3 5197078951970819 − GFM1 3 159853935 159853965 + ERCC1 19 50609045 50609075 −MSMB 10 51225827 51225857 + CGN 1 149764875 149764905 + STAT6 1255778539 55778569 − CACNA1G 17 46040364 46040394 + FAM176B 1 3656206536562095 − NT5C 17 70638855 70638885 − NEB 2 152054715 152054745 − MGAT52 134815785 134815815 + MTIF2 2 55349202 55349232 − SDK1 7 39755673975597 + CLEC16A 16 10974404 10974434 + RMND5B 5 177503319 177503349 +ADAMTS12 5 33685400 33685430 − HLA-G 6 29905434 29905464 + LOC389634 128434117 8434147 − HP1BP3 1 20975661 20975691 − TGM7 15 41356336 41356366− KIAA0564 13 41191711 41191741 − SLC6A13 12 217337 217367 − SLC6A6 314464313 14464343 + C11orf30 11 75911968 75911998 + NFKBIL2 8 145638852145638882 − DCUN1D4 4 52469883 52469913 + PRODH 22 17298487 17298517 −TEK 9 27159612 27159642 + CACNA1H 16 1202124 1202154 + RRP1B 21 4392063043920660 + INTS3 1 152003306 152003336 + MGC16169 4 107450517 107450547− POMT2 14 76842417 76842447 − TMEM77 1 111464661 111464691 − KLK12 1956226928 56226958 − ADCY3 2 24915204 24915234 − FAM134A 2 219754156219754186 + RALBP1 18 9503272 9503302 + MKKS 20 10360316 10360346 −EPHB2 1 23111664 23111694 + HPGD 4 175650861 175650891 − PDXK 2143996923 43996953 + FKBP3 14 44659824 44659854 − SLC22A17 14 2289167922891709 − TXNDC10 18 64501126 64501156 − GPR158 10 25724933 25724963 +NUP88 17 5230736 5230766 − LYN 8 57022821 57022851 + SV2C 5 7562289775622927 + SFRS12 5 65476106 65476136 + ADAM32 8 39222827 39222857 +DHRS9 2 169632008 169632038 + SEZ6 17 24307287 24307317 − CLK1 2201437053 201437083 − NUDT5 10 12277759 12277789 − SLC6A11 3 1084006210840092 + PDZRN3 3 73535973 73536003 − COL1A1 17 45631570 45631600 −TP53I3 2 24161089 24161119 − DVL3 3 185367140 185367170 + SCN8A 1250366493 50366523 + ITIH1 3 52796653 52796683 + NLRC3 16 3547579 3547609− NLRP8 19 61179466 61179496 + CDK6 7 92090270 92090300 − SNCAIP 5121808311 121808341 + RFT1 3 53128924 53128954 − SH3BGRL2 6 8044022080440250 + GSTCD 4 106966391 106966421 + PDE10A 6 165768699 165768729 −DAZ2 Y 23782988 23783018 + OPN4 10 88408409 88408439 + DAZ2 Y 2540822325408253 + C1orf87 1 60227396 60227426 − FCGBP 19 45124790 45124820 −EFNA4 1 153306525 153306555 + ZNF326 1 90245882 90245912 + KLHL20 1172011589 172011619 + ITPR2 12 26483311 26483341 − LAMA1 18 69484606948490 − CHL1 3 411540 411570 + BBS4 15 70804034 70804064 + NKAIN2 6124645972 124646002 + SUPT6H 17 24025743 24025773 + COL11A1 1 103121327103121357 − MEGF10 5 126797085 126797115 + CNGA3 2 98366321 98366351 +FGD6 12 94026394 94026424 − SYT6 1 114437864 114437894 − SMTN 2229825867 29825897 + ARHGAP26 5 142373859 142373889 + PBRM1 3 5267117352671203 − PTPRN2 7 157596266 157596296 − ATG16L2 11 72212800 72212830 +EPHA4 2 221999412 221999442 − KALRN 3 125859073 125859103 + RUFY1 5178936728 178936758 + DDEF1 8 131269521 131269551 − ATP13A5 3 194534217194534247 − CSTF3 11 33077714 33077744 − PELI2 14 55825090 55825120 +ARHGAP8 22 43576693 43576723 + BTAF1 10 93681242 93681272 + ZC3H7A 1611759772 11759802 − SIVA1 14 104294127 104294157 + LARP7 4 113777829113777859 + APOH 17 61655880 61655910 − EFTUD2 17 40318134 40318164 −TGS1 8 56848817 56848847 + UCK1 9 133391637 133391667 − CMYA5 5 7912263379122663 + CAPN3 15 40465431 40465461 + NLRP7 19 60141208 60141238 −CNTN6 3 1389143 1389173 + CYP24A1 20 52208016 52208046 − PARD3 1034730744 34730774 − B4GALNT3 12 439957 439987 + TAF2 8 120866606120866636 − UTP20 12 100203775 100203805 + TSPAN7 X 38310537 38310567 +NEK11 3 132475093 132475123 + TP53BP2 1 222038424 222038454 − CARKD 13110072699 110072729 + JMJD1C 10 64638813 64638843 − C15orf60 15 7163052971630559 + GRIA1 5 153058811 153058841 + PIP5K1A 1 149478263 149478293 +RNGTT 6 89567986 89568016 − NLRC5 16 55662016 55662046 + ABCC9 1221957057 21957087 − SCN2A 2 165872678 165872708 + SNX6 14 3416884834168878 − PITRM1 10 3192024 3192054 − CGNL1 15 55531764 55531794 + RRM111 4105047 4105077 + ITGAL 16 30429943 30429973 + PKIB 6 122996196122996226 + CYP4F3 19 15621076 15621106 + C9orf43 9 115225584115225614 + CYP4F2 19 15862106 15862136 − ADAM22 7 87630416 87630446 +MS4A13 11 60047987 60048017 + HCK 20 30126170 30126200 + C2orf55 298820998 98821028 − MRPL11 11 65961135 65961165 − AFP 4 7453403374534063 + COL2A1 12 46677640 46677670 − COL15A1 9 100851846 100851876 +TBPL1 6 134343076 134343106 + RIF1 2 152023655 152023685 + TM4SF20 2227943859 227943889 − RPS6KA6 X 83246147 83246177 − KIAA0528 12 2256761122567641 − DDX1 2 15670844 15670874 + C11orf65 11 107783017 107783047 −MPDZ 9 13129970 13130000 − PTPRT 20 40377761 40377791 − PGM2 4 3752665237526682 + ITFG1 16 46044129 46044159 − RBL2 16 52058567 52058597 +MAP2K1 15 64466804 64466834 + CCDC131 12 70294865 70294895 − HSF2BP 2143877565 43877595 − NDC80 18 2598814 2598844 + RFTN1 3 16394213 16394243− USH2A 1 214238836 214238866 − ITPR2 12 26759936 26759966 − VPS39 1540243100 40243130 − OBFC2A 2 192254973 192255003 + DMTF1 7 8664857886648608 + WDR16 17 9442360 9442390 + RNF11 1 51508370 51508400 + OPTN10 13191006 13191036 + DOCK10 2 225378003 225378033 − C14orf101 1456121488 56121518 + IQGAP2 5 75942749 75942779 + ADRBK2 22 2440486724404897 + NLRP13 19 61108104 61108134 − TOM1L2 17 17710899 17710929 −^(A) Homo sapiens (human) genome assembly GRCh37 (hg19) from GenomeReference ConsortiumMethods of Treatment

The compositions and methods described herein can be used for treating ahuman disease or disorder associated with aberrant splicing, such asaberrant pre-mRNA splicing. The compositions and methods describedherein can be used for treating a human disease or disorder bymodulating mRNA, such as pre-mRNA. In some embodiments, the compositionsand methods described herein can be used for treating a human disease ordisorder by modulating splicing of a nucleic acid even when that nucleicacid is not aberrantly spliced in the pathogenesis of the disease ordisorder being treated.

Provided herein are methods of treating cancer or a non-cancer diseaseor condition in a mammal in need thereof. The method can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof, to a mammal with acancer or a non-cancer disease or condition. In some embodiments, thepresent disclosure relates to the use of an SMSM as described herein forthe preparation of a medicament for the treatment, prevention and/ordelay of progression of cancer or a non-cancer disease or condition. Insome embodiments, the present disclosure relates to the use of a stericmodulator as described herein for the treatment, prevention and/or delayof progression of cancer or a non-cancer disease or condition.

In some embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof refers to an amount of anSMSM compound or a pharmaceutically acceptable salt thereof to a patientwhich has a therapeutic effect and/or beneficial effect. In certainspecific embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof to a patient results inone, two or more of the following effects: (i) reduces or amelioratesthe severity of a disease; (ii) delays onset of a disease; (iii)inhibits the progression of a disease; (iv) reduces hospitalization of asubject; (v) reduces hospitalization length for a subject; (vi)increases the survival of a subject; (vii) improves the quality of lifeof a subject; (viii) reduces the number of symptoms associated with adisease; (ix) reduces or ameliorates the severity of a symptomassociated with a disease; (x) reduces the duration of a symptomassociated with a disease associated; (xi) prevents the recurrence of asymptom associated with a disease; (xii) inhibits the development oronset of a symptom of a disease; and/or (xiii) inhibits of theprogression of a symptom associated with a disease. In some embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount of a RNAtranscript of a gene to the amount of the RNA transcript detectable inhealthy patients or cells from healthy patients. In other embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount an RNA isoformand/or protein isoform of gene to the amount of the RNA isoform and/orprotein isoform detectable in healthy patients or cells from healthypatients.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective todecrease the aberrant amount of an RNA transcript of a gene whichassociated with a disease. In some embodiments, an effective amount ofan SMSM compound or a pharmaceutically acceptable salt thereof is anamount effective to decrease the amount of the aberrant expression of anisoform of a gene. In some embodiments, an effective amount of an SMSMcompound or a pharmaceutically acceptable salt thereof is an amounteffective to result in a substantial change in the amount of an RNAtranscript (e.g., mRNA transcript), alternative splice variant orisoform.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective toincrease or decrease the amount of an RNA transcript (e.g., an mRNAtranscript) of gene which is beneficial for the prevention and/ortreatment of a disease. In some embodiments, an effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof is an amounteffective to increase or decrease the amount of an alternative splicevariant of an RNA transcript of gene which is beneficial for theprevention and/or treatment of a disease. In some embodiments, aneffective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to increase or decrease the amountof an isoform of gene which is beneficial for the prevention and/ortreatment of a disease.

A method of treating cancer in a subject in need thereof can compriseadministering to the subject a therapeutically effective amount of acompound described herein or a pharmaceutically acceptable salt thereof.A method of treating a non-cancer disease or condition in a subject inneed thereof can comprise administering to the subject a therapeuticallyeffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present disclosure relates to a method for thetreatment, prevention and/or delay of progression of cancer or anon-cancer disease or condition comprising administering an effectiveamount of a SMSM as described herein to a subject, in particular to amammal.

In some embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof refers to an amount of anSMSM compound or a pharmaceutically acceptable salt thereof to a patientwhich has a therapeutic effect and/or beneficial effect. In certainspecific embodiments, an effective amount in the context of theadministration of an SMSM compound or a pharmaceutically acceptable saltthereof, or composition or medicament thereof to a patient results inone, two or more of the following effects: (i) reduces or amelioratesthe severity of a disease; (ii) delays onset of a disease; (iii)inhibits the progression of a disease; (iv) reduces hospitalization of asubject; (v) reduces hospitalization length for a subject; (vi)increases the survival of a subject; (vii) improves the quality of lifeof a subject; (viii) reduces the number of symptoms associated with adisease; (ix) reduces or ameliorates the severity of a symptomassociated with a disease; (x) reduces the duration of a symptomassociated with a disease associated; (xi) prevents the recurrence of asymptom associated with a disease; (xii) inhibits the development oronset of a symptom of a disease; and/or (xiii) inhibits of theprogression of a symptom associated with a disease. In some embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount of a RNAtranscript of a gene to the amount of the RNA transcript detectable inhealthy patients or cells from healthy patients. In other embodiments,an effective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to restore the amount an RNA isoformand/or protein isoform of gene to the amount of the RNA isoform and/orprotein isoform detectable in healthy patients or cells from healthypatients.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective todecrease the aberrant amount of an RNA transcript of a gene whichassociated with a disease. In some embodiments, an effective amount ofan SMSM compound or a pharmaceutically acceptable salt thereof is anamount effective to decrease the amount of the aberrant expression of anisoform of a gene. In some embodiments, an effective amount of an SMSMcompound or a pharmaceutically acceptable salt thereof is an amounteffective to result in a substantial change in the amount of an RNAtranscript (e.g., mRNA transcript), alternative splice variant orisoform.

In some embodiments, an effective amount of an SMSM compound or apharmaceutically acceptable salt thereof is an amount effective toincrease or decrease the amount of an RNA transcript (e.g., an mRNAtranscript) of gene which is beneficial for the prevention and/ortreatment of a disease. In some embodiments, an effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof is an amounteffective to increase or decrease the amount of an alternative splicevariant of an RNA transcript of gene which is beneficial for theprevention and/or treatment of a disease. In some embodiments, aneffective amount of an SMSM compound or a pharmaceutically acceptablesalt thereof is an amount effective to increase or decrease the amountof an isoform of gene which is beneficial for the prevention and/ortreatment of a disease. Non-limiting examples of effective amounts of anSMSM compound or a pharmaceutically acceptable salt thereof aredescribed herein. For example, the effective amount may be the amountrequired to prevent and/or treat a disease associated with the aberrantamount of an mRNA transcript of gene in a human subject. In general, theeffective amount will be in a range of from about 0.001 mg/kg/day toabout 500 mg/kg/day for a patient having a weight in a range of betweenabout 1 kg to about 200 kg. The typical adult subject is expected tohave a median weight in a range of between about 70 and about 100 kg.

In one embodiment, an SMSM described herein can be used in thepreparation of medicaments for the treatment of diseases or conditionsdescribed herein. In addition, a method for treating any of the diseasesor conditions described herein in a subject in need of such treatment,can involve administration of pharmaceutical compositions that includesat least one SMSM described herein or a pharmaceutically acceptablesalt, thereof, in a therapeutically effective amount to a subject.

In certain embodiments, an SMSM described herein can be administered forprophylactic and/or therapeutic treatments. In certain therapeuticapplications, the compositions are administered to a patient alreadysuffering from a disease or condition, in an amount sufficient to cureor at least partially arrest at least one of the symptoms of the diseaseor condition. Amounts effective for this use depend on the severity andcourse of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. Therapeutically effective amounts are optionallydetermined by methods including, but not limited to, a dose escalationclinical trial. In prophylactic applications, compositions containing anSMSM described herein can be administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Incertain embodiments, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). Doses employed for adult human treatmenttypically range of 0.01 mg-5000 mg per day or from about 1 mg to about1000 mg per day. In some embodiments, a desired dose is convenientlypresented in a single dose or in divided doses.

For combination therapies described herein, dosages of theco-administered compounds can vary depending on the type of co-drug(s)employed, on the specific drug(s) employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially. If administration issimultaneous, the multiple therapeutic agents can be, by way of exampleonly, provided in a single, unified form, or in multiple forms.

Conditions and Diseases

The present disclosure relates to a pharmaceutical compositioncomprising a SMSM described herein for use in the treatment, preventionand/or delay of progression of a disease, disorder or condition. In someembodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a SMSM described herein for use in the treatment,prevention and/or delay of progression of a disease, disorder orcondition in Table 2A, Table 2B, Table 2C and Table 2D.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with a disease, disorder or condition in Table2A, Table 2B, Table 2C and Table 2D.

In some embodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a SMSM described herein for use in the treatment,prevention and/or delay of progression of cancer.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with aliquid cancer. A method of treating, preventing, or delaying cancer cancomprise administering a therapeutically effective amount of a compounddescribed herein or a pharmaceutically acceptable salt thereof to asubject with a leukemia or lymphoma. A method of treating, preventing,or delaying cancer can comprise administering a therapeuticallyeffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof to a subject with a leukemia, acute myeloidleukemia, colon cancer, gastric cancer, macular degeneration, acutemonocytic leukemia, breast cancer, hepatocellular carcinoma, cone-roddystrophy, alveolar soft part sarcoma, myeloma, skin melanoma,prostatitis, pancreatitis, pancreatic cancer, retinitis, adenocarcinoma,adenoiditis, adenoid cystic carcinoma, cataract, retinal degeneration,gastrointestinal stromal tumor, Wegener's granulomatosis, sarcoma,myopathy, prostate adenocarcinoma, Hodgkin's lymphoma, ovarian cancer,non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia,acute lymphoblastic leukemia, renal cell carcinoma, transitional cellcarcinoma, colorectal cancer, chronic lymphocytic leukemia, anaplasticlarge cell lymphoma, kidney cancer, breast cancer, cervical cancer.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with asolid cancer or solid tumor.

In some embodiments, the tumor is selected from the group consisting ofadenocarcinoma, melanoma (e.g., metastatic melanoma), liver cancer(e.g., hepatocellular carcinoma, hepatoblastoma, liver carcinoma),prostate cancer (e.g., prostate adenocarcinoma, androgen-independentprostate cancer, androgen-dependent prostate cancer, prostatecarcinoma), sarcoma (e.g., leiomyosarcoma, rhabdomyosarcoma), braincancer (e.g., glioma, a malignant glioma, astrocytoma, brain stemglioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, primary brain lymphoma, anaplastic astrocytoma, juvenilepilocytic astrocytoma, a mixture of oligodendroglioma and astrocytomaelements), breast cancer (e.g., triple negative breast cancer,metastatic breast cancer, breast carcinoma, breast sarcoma,adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma,medullary breast cancer, mucinous breast cancer, tubular breast cancer,papillary breast cancer, inflammatory breast cancer), Paget's disease,juvenile Paget's disease, lung cancer (e.g., KRAS-mutated non-small celllung cancer, non-small cell lung cancer, squamous cell carcinoma(epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, small celllung cancer, lung carcinoma), pancreatic cancer (e.g., insulinoma,gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, carcinoidtumor, islet cell tumor, pancreas carcinoma), skin cancer (e.g., skinmelanoma, basal cell carcinoma, squamous cell carcinoma, melanoma,superficial spreading melanoma, nodular melanoma, lentigo malignantmelanoma, acrallentiginous melanoma, skin carcinoma), cervical cancer(e.g., squamous cell carcinoma, adenocarcinoma, cervical carcinoma),ovarian cancer (e.g., ovarian epithelial carcinoma, borderline tumor,germ cell tumor, stromal tumor, ovarian carcinoma), cancer of the mouth,cancer of the nervous system (e.g., cancer of the central nervoussystem, a CNS germ cell tumor), goblet cell metaplasia, kidney cancer(e.g., renal cell cancer, adenocarcinoma, hypernephroma, Wilms' tumor,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer),renal cell carcinoma, renal carcinoma), bladder cancer (e.g.,transitional cell carcinoma, squamous cell cancer, carcinosarcoma),stomach cancer (e.g., fungating (polypoid), ulcerating, superficialspreading, diffusely spreading, liposarcoma, fibrosarcoma,carcinosarcoma), uterine cancer (e.g., endometrial cancer, endometrialcarcinoma, uterine sarcoma), cancer of the esophagus (e.g., squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell (small cell) carcinoma, esophagealcarcinomas), colon cancer (e.g., colon carcinoma), cancer of the rectum(e.g., rectal cancers), colorectal cancer (e.g., colorectal carcinoma,metastatic colorectal cancer, hereditary nonpolyposis colorectal cancer,KRAS mutated colorectal cancer), gallbladder cancer (e.g.,adenocarcinoma, cholangiocarcinoma, papillary cholangiocarcinoma,nodular cholangiocarcinoma, diffuse cholangiocarcinoma), testicularcancer (e.g., germinal tumor, seminoma, anaplastic testicular cancer,classic (typical) testicular cancer, spermatocytic testicular cancer,nonseminoma testicular cancer), embryonal carcinoma (e.g., teratomacarcinoma, choriocarcinoma (yolk-sac tumor)), gastric cancer (e.g.,gastrointestinal stromal tumor, cancer of other gastrointestinal tractorgans, gastric carcinomas), bone cancer (e.g., connective tissuesarcoma, bone sarcoma, cholesteatoma-induced bone osteosarcoma, Paget'sdisease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma,malignant giant cell tumor, fibrosarcoma of bone, chordoma, periostealsarcoma, soft-tissue sarcoma, angiosarcoma (hemangiosarcoma),fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, alveolar soft partsarcoma), liposarcoma, lymphangiosarcoma, neurilemmoma,rhabdomyosarcoma, synovial sarcoma, cancer of the lymph node (e.g.,lymphangioendotheliosarcoma), adenoid cystic carcinoma, vaginal cancer(e.g., squamous cell carcinoma, adenocarcinoma, melanoma), vulvar cancer(e.g., squamous cell carcinoma, melanoma, adenocarcinoma, sarcoma,Paget's disease), cancer of other reproductive organs, thyroid cancer(e.g., papillary thyroid cancer, follicular thyroid cancer, medullarythyroid cancer, anaplastic thyroid cancer, thyroid carcinoma), salivarygland cancer (e.g., adenocarcinoma, mucoepidermoid carcinoma), eyecancer (e.g., ocular melanoma, iris melanoma, choroidal melanoma,cilliary body melanoma, retinoblastoma), penal cancers, oral cancer(e.g. squamous cell carcinoma, basal cancer), pharynx cancer (e.g.,squamous cell cancer, verrucous pharynx cancer), cancer of the head,cancer of the neck, cancer of the throat, cancer of the chest, cancer ofthe spleen, cancer of skeletal muscle, cancer of subcutaneous tissue,adrenal cancer, pheochromocytoma, adrenocortical carcinoma, pituitarycancer, Cushing's disease, prolactin-secreting tumor, acromegaly,diabetes insipidus, myxosarcoma, osteogenic sarcoma, endotheliosarcoma,mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma,cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, ependyoma, optic nerve glioma, primitiveneuroectodermal tumor, rhabdoid tumor, renal cancer, glioblastomamultiforme, neurofibroma, neurofibromatosis, pediatric cancer,neuroblastoma, malignant melanoma, carcinoma of the epidermis,polycythemia vera, Waldenstrom's macroglobulinemia, monoclonalgammopathy of undetermined significance, benign monoclonal gammopathy,heavy chain disease, pediatric solid tumor, Ewing's sarcoma, Wilmstumor, carcinoma of the epidermis, HIV-related Kaposi's sarcoma,rhabdomyosarcoma, thecomas, arrhenoblastomas, endometrial carcinoma,endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma,nasopharyngeal carcinoma, laryngeal carcinoma, hepatoblastoma, Kaposi'ssarcoma, hemangioma, cavernous hemangioma, hemangioblastoma,retinoblastoma, glioblastoma, Schwannoma, neuroblastoma,rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, urinary tractcarcinoma, abnormal vascular proliferation associated with phakomatoses,edema (such as that associated with brain tumors), Meigs' syndrome,pituitary adenoma, primitive neuroectodermal tumor, medullblastoma, andacoustic neuroma.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject withbasal cell carcinoma, goblet cell metaplasia, or a malignant glioma. Amethod of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with acancer of the liver, breast, lung, prostate, cervix, uterus, colon,pancreas, kidney, stomach, bladder, ovary, or brain.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with acancer of the head, neck, eye, mouth, throat, esophagus, esophagus,chest, bone, lung, kidney, colon, rectum or other gastrointestinal tractorgans, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate,breast, ovaries, testicles or other reproductive organs, skin, thyroid,blood, lymph nodes, kidney, liver, pancreas, and brain or centralnervous system.

Specific examples of cancers that can be prevented and/or treated inaccordance with present disclosure include, but are not limited to, thefollowing: renal cancer, kidney cancer, glioblastoma multiforme,metastatic breast cancer; breast carcinoma; breast sarcoma;neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma;malignant melanoma; carcinomas of the epidermis; leukemias such as butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplasticsyndrome, chronic leukemias such as but not limited to, chronicmyelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairycell leukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's disease, non-Hodgkin's disease; multiple myelomas such as butnot limited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone cancer and connective tissue sarcomas such asbut not limited to bone sarcoma, myeloma bone disease, multiple myeloma,cholesteatoma-induced bone osteosarcoma, Paget's disease of bone,osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant celltumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma,rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but notlimited to, glioma, astrocytoma, brain stem glioma, ependymoma,oligodendroglioma, nonglial tumor, acoustic neurinoma,craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; breast cancer including butnot limited to adenocarcinoma, lobular (small cell) carcinoma,intraductal carcinoma, medullary breast cancer, mucinous breast cancer,tubular breast cancer, papillary breast cancer, Paget's disease(including juvenile Paget's disease) and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipius; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; cervicalcarcinoma; esophageal cancers such as but not limited to, squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell(small cell) carcinoma; stomach cancerssuch as but not limited to, adenocarcinoma, fungating (polypoid),ulcerating, superficial spreading, diffusely spreading, malignantlymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers;KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; livercancers such as but not limited to hepatocellular carcinoma andhepatoblastoma, gallbladder cancers such as adenocarcinoma;cholangiocarcinomas such as but not limited to papillary, nodular, anddiffuse; lung cancers such as KRAS-mutated non-small cell lung cancer,non-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; lung carcinoma; testicular cancers such as but not limited togerminal tumor, seminoma, anaplastic, classic (typical), spermatocytic,nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma(yolk-sac tumor), prostate cancers such as but not limited to,androgen-independent prostate cancer, androgen-dependent prostatecancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penalcancers; oral cancers such as but not limited to squamous cellcarcinoma; basal cancers; salivary gland cancers such as but not limitedto adenocarcinoma, mucoepidermoid carcinoma, and adenoidcysticcarcinoma; pharynx cancers such as but not limited to squamous cellcancer, and verrucous; skin cancers such as but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma,acrallentiginous melanoma; kidney cancers such as but not limited torenal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma,transitional cell cancer (renal pelvis and/or uterer); renal carcinoma;Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma,hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillarycarcinoma and papillary adenocarcinomas.

A method of treating, preventing, or delaying cancer can compriseadministering a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof to a subject with apediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma,neurofibroma, carcinoma of the epidermis, malignant melanoma, cervicalcarcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breastcarcinoma, breast sarcoma, metastatic breast cancer, HIV-relatedKaposi's sarcoma, prostate cancer, androgen-independent prostate cancer,androgen-dependent prostate cancer, neurofibromatosis, lung cancer,non-small cell lung cancer, KRAS-mutated non-small cell lung cancer,malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectalcancer, glioblastoma multiforme, renal cancer, kidney cancer, bladdercancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma,rhabdomyosarcoma, acute myeloid leukemia, or multiple myeloma.

In some embodiments, cancers and conditions associated therewith thatare prevented and/or treated in accordance with the present disclosureare breast carcinomas, lung carcinomas, gastric carcinomas, esophagealcarcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas,thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma,endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma,head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas,hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma,cavernous hemangioma, hemangioblastoma, pancreas carcinomas,retinoblastoma, astrocytoma, glioblastoma, Schwannoma,oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma,osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroidcarcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma,abnormal vascular proliferation associated with phakomatoses, edema(such as that associated with brain tumors), or Meigs' syndrome. Inspecific embodiment, the cancer an astrocytoma, an oligodendroglioma, amixture of oligodendroglioma and an astrocytoma elements, an ependymoma,a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, amedullblastoma, a primary central nervous system (CNS) lymphoma, or aCNS germ cell tumor.

In some embodiments, the cancer treated in accordance with the presentdisclosure is an acoustic neuroma, an anaplastic astrocytoma, aglioblastoma multiforme, or a meningioma. In some embodiments, thecancer treated in accordance with the present disclosure is a brain stemglioma, a craniopharyngioma, an ependyoma, a juvenile pilocyticastrocytoma, a medulloblastoma, an optic nerve glioma, primitiveneuroectodermal tumor, or a rhabdoid tumor.

A method of treating, preventing, or delaying a condition or disease cancomprise administering a therapeutically effective amount of a compounddescribed herein or a pharmaceutically acceptable salt thereof to asubject with acute myeloid leukemia, ALS, Alzheimer's disease,argyrophilic grain disease, cancer metabolism, chronic lymphocyticleukemia, colorectal carcinoma, corticobasal degeneration, cysticfibrosis, dilated cardiomyopathy, Duchenne muscular dystrophy,Ehlers-Danlos syndrome, endometrial cancer, Fabry's disease, familialdysautonomia, familial hypercholesterolemia, familial persistenthyperinsulinemic hypoglycemia, frontotemporal dementia, FTDP-17,gucher's disease, glioma, globular glial tauopathy, HIV-1, Huntington'sdisease, Hutchinson-Gilford progeria syndrome, hypercholesterolemia,Leber congenital amaurosis, migraine, multiple sclerosis,myelodysplastic syndromes, NASH, Niemann-Pick's, non-small cell lungcancer, pain, Parkinson's disease, phenylketonuria, Pick's disease,progressive supranuclear palsy, spinal muscular atrophy, spinocerebellarataxia type 2, or Wilson's disease.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with atypical hemolytic uremic syndrome(aHUS), cystic fibrosis, muscular dystrophy, polycysticautosomal-dominant kidney disease, cancer-induced cachexia, benignprostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis,obesity, retinopathies (including diabetic retinopathy and retinopathyof prematurity), retrolental fibroplasia, neovascular glaucoma,age-related macular degeneration, exudative macular degeneration,thyroid hyperplasias (including Grave's disease), corneal and othertissue transplantation, epidemic keratoconjunctivitis, Vitamin Adeficiency, contact lens overwear, atopic keratitis, superior limbickeratitis, and pterygium keratitis sicca, viral infections, inflammationassociated with viral infections, chronic inflammation, lunginflammation, nephrotic syndrome, preeclampsia, ascites, pericardialeffusion (such as that associated with pericarditis), pleural effusion,Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, lipiddegeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpessimplex infection, Herpes zoster infections, protozoan infections,Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis,systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, Paget'sdisease, scleritis, Stevens-Johnson's disease, pemphigoid, radialkeratotomy, Eales' disease, Behcet's disease, sickle cell anemia,pseudoxanthoma elasticum, Stargardt's disease, pars planitis, chronicretinal detachment, vein occlusion, artery occlusion, carotidobstructive disease, chronic uveitis/vitritis, ocular histoplasmosis,Mycobacteria infections, Lyme's disease, Best's disease, myopia, opticpits, hyperviscosity syndromes, toxoplasmosis, sarcoidosis, trauma,post-laser complications, diseases associated with rubeosis(neovascularization of the iris and of the angle), and diseases causedby the abnormal proliferation of fibrovascular or fibrous tissue,including all forms of prolific vitreoretinopathy. Certain examples ofnon-neoplastic conditions that can be prevented and/or treated inaccordance with the methods described herein include viral infections,including but not limited to, those associated with viruses belonging toFlaviviridae, flavivirus, pestivirus, hepacivirus, West Nile virus,hepatitis C virus (HCV) or human papilloma virus (HPV), cone-roddystrophy, prostatitis, pancreatitis, retinitis, cataract, retinaldegeneration, Wegener's granulomatosis, myopathy, adenoiditis, germ celltumors, combined methylmalonic aciduria and homocystinuria, cblC type,Alzheimer's disease, hyperprolinemia, acne, tuberculosis, succinicsemialdehyde dehydrogenase deficiency, esophagitis, mental retardation,glycine encephalopathy, Crohn's disease, spina bifida, autosomalrecessive disease, schizophrenia, neural tube defects, myelodysplasticsyndromes, amyotropic lateral sclerosis, neuronitis, Parkinson'sdisease, talipes equinovarus, dystrophinopathies, cerebritis, bladderrelated disorders, cleft lip, cleft palate, cervicitis, spasticity,lipoma, scleroderma, Gitelman syndrome, poliomyelitis, paralysis,Aagenaes syndrome, oculomotor nerve paralysis, and spinal muscularatrophy.

A method of treating, preventing, or delaying a non-cancer disease orcondition disease can comprise administering a therapeutically effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof to a subject with atypical hemolytic uremic syndrome(aHUS), Hutchinson-Gilford progeria syndrome (HGPS), Limb girdlemuscular dystrophy type 1B, Familial partial lipodystrophy type 2,Frontotemporal dementia with parkinsonism chromosome 17, Richardson'ssyndrome, PSP-Parkinsonism, Argyrophilic grain disease, Corticobasaldegeneration, Pick's disease, Globular glial tauopathy, GuadeloupeanParkinsonism, Myotonic dystrophy, Down Syndrome, NeonatalHypoxia-Ischemia, Familial Dysautonomia, Spinal muscular atrophy,Hypoxanthine phosphoribosyltransferase deficiency, Ehlers-Danlossyndrome, Occipital Horn Syndrome, Fanconi Anemia, Marfan Syndrome,thrombotic thrombocytopenic purpura, glycogen Storage Disease Type III,cystic fibrosis, neurofibromatosis, Tyrosinemia (type I), MenkesDisease, Analbuminemia, Congenital acetylcholinesterase deficiency,Haemophilia B deficiency (coagulation factor IX deficiency), Recessivedystrophic epidermolysis bullosa, Dominant dystrophic epidermolysisbullosa, Somatic mutations in kidney tubular epithelial cells,Neurofibromatosis type II, X-linked adrenoleukodystrophy (X-ALD), FVIIdeficiency, Homozygous hypobetalipoproteinemia, Ataxia-telangiectasia,Androgen Sensitivity, Common congenital afibrinogenemia, Risk foremphysema, Mucopolysaccharidosis type II (Hunter syndrome), Severe typeIII osteogenesis imperfecta, Ehlers-Danlos syndrome IV, Glanzmannthrombasthenia, Mild Bethlem myopathy, Dowling-Meara epidermolysisbullosa simplex, Severe deficiency of MTHFR, Acute intermittentporphyria, Tay-Sachs Syndrome, Myophosphorylase deficiency (McArdledisease), Chronic Tyrosinemia Type 1, Mutation in placenta, Leukocyteadhesion deficiency, Hereditary C3 deficiency, Neurofibromatosis type I,Placental aromatase deficiency, Cerebrotendinous xanthomatosis, Duchenneand Becker muscular dystrophy, Severe factor V deficiency,Alpha-thalassemia, Beta-thalassemia, Hereditary HL deficiency,Lesch-Nyhan syndrome, Familial hypercholesterolemia, Phosphoglyceratekinase deficiency, Cowden syndrome, X-linked retinitis pigmentosa (RP3),Crigler-Najjar syndrome type 1, Chronic tyrosinemia type I, Sandhoffdisease, Maturity onset diabetes of the young (MODY), Familial tuberoussclerosis, Polycystic kidney disease 1, or Primary Hyperthyroidism.

In some embodiments, non-cancer diseases that can be prevented and/ortreated in accordance with the disclosure of WO2016/196386 a1,WO2016/128343 a1, WO2015/024876 a2 and EP3053577A1. In some embodiments,non-cancer diseases that can be prevented and/or treated include, butare not limited to, atypical hemolytic uremic syndrome (aHUS),Hutchinson-Gilford progeria syndrome (HGPS), Limb girdle musculardystrophy type 1B, Familial partial lipodystrophy type 2, Frontotemporaldementia with parkinsonism chromosome 17, Richardson's syndrome,PSP-Parkinsonism, Argyrophilic grain disease, Corticobasal degeneration,Pick's disease, Globular glial tauopathy, Guadeloupean Parkinsonism,Myotonic dystrophy, Down Syndrome, Neonatal Hypoxia-Ischemia, FamilialDysautonomia, Spinal muscular atrophy, Hypoxanthinephosphoribosyltransferase deficiency, Ehlers-Danlos syndrome, OccipitalHorn Syndrome, Fanconi Anemia, Marfan Syndrome, thromboticthrombocytopenic purpura, glycogen Storage Disease Type III, cysticfibrosis, neurofibromatosis, Tyrosinemia (type I), Menkes Disease,Analbuminemia, Congenital acetylcholinesterase deficiency, Haemophilia Bdeficiency (coagulation factor IX deficiency), Recessive dystrophicepidermolysis bullosa, Dominant dystrophic epidermolysis bullosa,Somatic mutations in kidney tubular epithelial cells, Neurofibromatosistype II, X-linked adrenoleukodystrophy (X-ALD), FVII deficiency,Homozygous hypobetalipoproteinemia, Ataxia-telangiectasia, AndrogenSensitivity, Common congenital afibrinogenemia, Risk for emphysema,Mucopolysaccharidosis type II (Hunter syndrome), Severe type IIIosteogenesis imperfecta, Ehlers-Danlos syndrome IV, Glanzmannthrombasthenia, Mild Bethlem myopathy, Dowling-Meara epidermolysisbullosa simplex, Severe deficiency of MTHFR, Acute intermittentporphyria, Tay-Sachs Syndrome, Myophosphorylase deficiency (McArdledisease), Chronic Tyrosinemia Type 1, Mutation in placenta, Leukocyteadhesion deficiency, Hereditary C3 deficiency, Neurofibromatosis type I,Placental aromatase deficiency, Cerebrotendinous xanthomatosis, Duchenneand Becker muscular dystrophy, Severe factor V deficiency,Alpha-thalassemia, Beta-thalassemia, Hereditary HL deficiency,Lesch-Nyhan syndrome, Familial hypercholesterolemia, Phosphoglyceratekinase deficiency, Cowden syndrome, X-linked retinitis pigmentosa (RP3),Crigler-Najjar syndrome type 1, Chronic tyrosinemia type I, Sandhoffdisease, Maturity onset diabetes of the young (MODY), Familial tuberoussclerosis, or Polycystic kidney disease 1.

Methods of Administering

The compositions described herein can be administered to the subject ina variety of ways, including parenterally, intravenously, intradermally,intramuscularly, colonically, rectally or intraperitoneally. In someembodiments, the small molecule splicing modulator or a pharmaceuticallyacceptable salt thereof is administered by intraperitoneal injection,intramuscular injection, subcutaneous injection, or intravenousinjection of the subject. In some embodiments, the pharmaceuticalcompositions can be administered parenterally, intravenously,intramuscularly or orally. The oral agents comprising a small moleculesplicing modulator can be in any suitable form for oral administration,such as liquid, tablets, capsules, or the like. The oral formulationscan be further coated or treated to prevent or reduce dissolution instomach. The compositions of the present invention can be administeredto a subject using any suitable methods known in the art. Suitableformulations for use in the present invention and methods of deliveryare generally well known in the art. For example, the small moleculesplicing modulators described herein can be formulated as pharmaceuticalcompositions with a pharmaceutically acceptable diluent, carrier orexcipient. The compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionsincluding pH adjusting and buffering agents, tonicity adjusting agents,wetting agents and the like, such as, for example, sodium acetate,sodium lactate, sodium chloride, potassium chloride, calcium chloride,sorbitan monolaurate, triethanolamine oleate, etc.

Pharmaceutical formulations described herein can be administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the pharmaceutical compositions described hereinare administered orally. In some embodiments, the pharmaceuticalcompositions described herein are administered topically. In suchembodiments, the pharmaceutical compositions described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, shampoos, scrubs,rubs, smears, medicated sticks, medicated bandages, balms, creams orointments. In some embodiments, the pharmaceutical compositionsdescribed herein are administered topically to the skin. In someembodiments, the pharmaceutical compositions described herein areadministered by inhalation. In some embodiments, the pharmaceuticalcompositions described herein are formulated for intranasaladministration. Such formulations include nasal sprays, nasal mists, andthe like. In some embodiments, the pharmaceutical compositions describedherein are formulated as eye drops. In some embodiments, thepharmaceutical compositions described herein are: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation to the mammal; and/or (e) administered bynasal administration to the mammal; or and/or (f) administered byinjection to the mammal; and/or (g) administered topically to themammal; and/or (h) administered by ophthalmic administration; and/or (i)administered rectally to the mammal; and/or (j) administerednon-systemically or locally to the mammal. In some embodiments, thepharmaceutical compositions described herein are administered orally tothe mammal. In certain embodiments, an SMSM described herein isadministered in a local rather than systemic manner. In someembodiments, an SMSM described herein is administered topically. In someembodiments, an SMSM described herein is administered systemically.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

SMSMs suitable for injectable use include sterile aqueous solutions(where water soluble) or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL™ (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, thecomposition must be sterile and should be fluid to the extent that easysyringability exists. It must be stable under the conditions ofmanufacture and storage and must be preserved against contamination frommicroorganisms such as bacteria and fungi. The carrier can be a solventor dispersion medium containing, for example, water, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyethyleneglycol, and the like), and suitable mixtures thereof. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmanitol, sorbitol, sodium chloride in the composition.

Dosing and Schedules

The SMSMs utilized in the methods of the invention can be, e.g.,administered at dosages that may be varied depending upon therequirements of the subject the severity of the condition being treatedand/or imaged, and/or the SMSM being employed. For example, dosages canbe empirically determined considering the type and stage of diseasediagnosed in a particular subject and/or the type of imaging modalitybeing used in conjunction with the SMSMs. The dose administered to asubject, in the context of the present invention should be sufficient toaffect a beneficial diagnostic or therapeutic response in the subject.The size of the dose also can be determined by the existence, nature,and extent of any adverse side-effects that accompany the administrationof a SMSM in a particular subject.

It is advantageous to formulate compositions in dosage unit form forease of administration and uniformity of dosage. Dosage unit form asused herein refers to physically discrete units suited as unitarydosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.Toxicity and therapeutic efficacy of such compounds can be determined byprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex and it can be expressed as the ratio LD₅₀/ED₅₀. Compounds thatexhibit large therapeutic indices are preferred. While compounds thatexhibit toxic side effects may be used, care should be taken to design adelivery system that targets such compounds to the site of affectedtissue to minimize potential damage to uninfected cells and, thereby,reduce side effects.

Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in predicting the therapeutic index in vivo andformulating a range of dosages for use in subjects, such as humansubjects. The data obtained from the cell culture assays and animalstudies can be used in formulating a range of dosage for use in humans.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For anycompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range that includes the concentration of the test compoundwhich achieves a half-maximal inhibition of symptoms as determined incell culture. Such information can be used to more accurately determineuseful doses in humans. Levels in plasma may be measured, for example,by high performance liquid chromatography. Various animal models andclinical assays for evaluating effectiveness of a particular SMSM inpreventing or reducing a disease or condition are known in the art maybe used in the present invention. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient'scondition. (See e.g. Fingl et al, 1975, In: The Pharmacological Basis ofTherapeutics. Ch. 1 pi).

In some aspects, the SMSMs provided have a therapeutic index (LD₅₀/ED₅₀)of at least about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,700, 800, 900, 1000, 10000, or 100000 or more. In some aspects, theSMSMs provided have a therapeutic index (LD₅₀/ED₅₀) of at least about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 40,50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000,10000, or 100000 or more as determined in cell culture.

In some aspects, the SMSMs provided have an IC₅₀ viability/EC₅₀ splicingvalue of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 10000, or 100000 or more. In some aspects, theSMSMs provided have an IC₅₀ viability/EC₅₀ splicing value of at leastabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900,1000, 10000, or 100000 or more as determined in cell culture.

A dosage of using an SMSM when administered may be at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 grams/m² inhumans, or a dosage in another subject comparable to that in humans. Adosage (“dosage X”) of an SMSM in a subject other than a human iscomparable to a dosage (“dosage Y”) of the SMSM in humans if the serumconcentration of the scavenger in the subject post administration of theSMSM at dosage X is equal to the serum concentration of the SMSM inhumans post administration of the compound at dosage Y.

Within the scope of the present description, the effective amount of anSMSM compound or a pharmaceutically acceptable salt thereof for use inthe manufacture of a medicament, the preparation of a pharmaceutical kitor in a method for preventing and/or treating a disease in a humansubject in need thereof, is intended to include an amount in a range offrom about 1 gg to about 50 grams.

The compositions of the present invention can be administered asfrequently as necessary, including hourly, daily, weekly or monthly.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of an effective amount of an SMSM describedherein, including further embodiments in which (i) the compound isadministered once; (ii) the compound is administered to the mammalmultiple times over the span of one day; (iii) continually; or (iv)continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of an SMSM describedherein, including further embodiments in which (i) the compound isadministered continuously or intermittently: as in a single dose; (ii)the time between multiple administrations is every 6 hours; (iii) thecompound is administered to the mammal every 8 hours; (iv) the compoundis administered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours.

In further or alternative embodiments, the method comprises a drugholiday, wherein the administration of an SMSM described herein istemporarily suspended or the dose of the compound being administered istemporarily reduced; at the end of the drug holiday, dosing of thecompound is resumed. In one embodiment, the length of the drug holidayvaries from 2 days to 1 year.

Combination Therapies

In certain instances, it is appropriate to administer at least one SMSMdescribed herein in combination with another therapeutic agent. Forexample, a compound SMSM described herein can be co-administered with asecond therapeutic agent, wherein SMSM and the second therapeutic agentmodulate different aspects of the disease, disorder or condition beingtreated, thereby providing a greater overall benefit than administrationof either therapeutic agent alone.

In some embodiments, an SMSM described herein can be used in combinationwith an anti-cancer therapy. In some embodiments, a steric modulator isused in combination with conventional chemotherapy, radiotherapy,hormonal therapy, and/or immunotherapy. In some embodiments, an SMSMdescribed herein can be used in combination with conventionalchemotherapeutic agents including alkylating agents (e.g., temozolomide,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.),anti-metabolites (e.g., 5-fluorouracil, azathioprine, methotrexate,leucovorin, capecitabine, cytarabine, floxuridine, fludarabine,gemcitabine, pemetrexed, raltitrexed, etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), EGFR inhibitors (e.g.,gefitinib, erlotinib, etc.), and the like.

In some embodiments, an SMSM may be administered in combination with oneor more other SMSMs.

A SMSM may be administered to a subject in need thereof prior to,concurrent with, or following the administration of chemotherapeuticagents. For instance, SMSMs may be administered to a subject at least 8hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours,1 hour, or 30 minutes before the starting time of the administration ofchemotherapeutic agent(s). In certain embodiments, they may beadministered concurrent with the administration of chemotherapeuticagent(s). In other words, in these embodiments, SMSMs are administratedat the same time when the administration of chemotherapeutic agent(s)starts. In other embodiments, SMSMs may be administered following thestarting time of administration of chemotherapeutic agent(s) (e.g., atleast 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours or 8 hours after the starting time of administration ofchemotherapeutic agents). Alternatively, SMSMs may be administered atleast 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours or 8 hours after the completion of administration ofchemotherapeutic agents. Generally, these SMSMs are administered for asufficient period of time so that the disease or condition is preventedor reduced. Such sufficient period of time may be identical to, ordifferent from, the period during which chemotherapeutic agent(s) areadministered. In certain embodiments, multiple doses of SMSMs areadministered for each administration of a chemotherapeutic agent or acombination of multiple chemotherapeutic agents.

In certain embodiments, an appropriate dosage of a SMSM is combined witha specific timing and/or a particular route to achieve the optimumeffect in preventing or reducing the disease or condition. For instance,an SMSM may be administered to a human orally at least 1 hour, 2 hours,3 hours, 4 hours, 5 hours, 6 hours, 7 hours 8 hours, 9 hours, 10 hours,11 hours or 12 hours; or at least 1 day, 2 days, 3 days, 4 days, 5 days,6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days; or at least 1week, 2 weeks, 3 weeks or 4 weeks; or at least 1 month, 2 months, 3months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10months, 11 months or 12 months; prior to or after the beginning or thecompletion, of the administration of a chemotherapeutic agent or acombination of chemotherapeutic agents.

Subjects

The subjects that can be treated with the SMSMs and methods describedherein can be any subject that produces mRNA that is subject toalternative splicing, e.g., the subject may be a eukaryotic subject,such as a plant or an animal. In some embodiments, the subject is amammal, e.g., human. In some embodiments, the subject is a human. Insome embodiments, the subject is a non-human animal. In someembodiments, the subject is a fetus, an embryo, or a child. In someembodiments, the subject is a non-human primate such as chimpanzee, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like.

In some embodiments, the subject is prenatal (e.g., a fetus), a child(e.g., a neonate, an infant, a toddler, a preadolescent), an adolescent,a pubescent, or an adult (e.g., an early adult, a middle aged adult, asenior citizen). The human subject can be between about 0 months andabout 120 years old, or older. The human subject can be between about 0and about 12 months old; for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 months old. The human subject can be between about 0 and12 years old; for example, between about 0 and 30 days old; betweenabout 1 month and 12 months old; between about 1 year and 3 years old;between about 4 years and 5 years old; between about 4 years and 12years old; about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. Thehuman subject can be between about 13 years and 19 years old; forexample, about 13, 14, 15, 16, 17, 18, or 19 years old. The humansubject can be between about 20 and about 39 year old; for example,about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, or 39 years old. The human subject can be between about 40to about 59 years old; for example, about 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years old. Thehuman subject can be greater than 59 years old; for example, about 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, or 120 years old. The humansubjects can include living subjects or deceased subjects.

The human subjects can include male subjects and/or female subjects.

Assays

Gene expression experiments often involve measuring the relative amountof gene expression products, such as mRNA, expressed in two or moreexperimental conditions. This is because altered levels of a specificsequence of a gene expression product can suggest a changed need for theprotein coded for by the gene expression product, perhaps indicating ahomeostatic response or a pathological condition.

In some embodiments, a method can comprise measuring, assaying orobtaining expression levels of one or more genes. In some cases, themethod provides a number or a range of numbers, of genes that theexpression levels of the genes can be used to diagnose, characterize orcategorize a biological sample. In some embodiments, the gene expressiondata corresponds to data of an expression level of one or morebiomarkers that are related to a disease or condition. The number ofgenes used can be between about 1 and about 500; for example about1-500, 1-400, 1-300, 1-200, 1-100, 1-50, 1-25, 1-10, 10-500, 10-400,10-300, 10-200, 10-100, 10-50, 10-25, 25-500, 25-400, 25-300, 25-200,25-100, 25-50, 50-500, 50-400, 50-300, 50-200, 50-100, 100-500, 100-400,100-300, 100-200, 200-500, 200-400, 200-300, 300-500, 300-400, 400-500,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210,220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350,360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490,500, or any included range or integer. For example, at least about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 33, 35, 38, 40, 43, 45, 48, 50,53, 58, 63, 65, 68, 100, 120, 140, 142, 145, 147, 150, 152, 157, 160,162, 167, 175, 180, 185, 190, 195, 200, 300, 400, 500 or more totalgenes can be used. The number of genes used can be less than or equal toabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 33, 35, 38, 40, 43,45, 48, 50, 53, 58, 63, 65, 68, 100, 120, 140, 142, 145, 147, 150, 152,157, 160, 162, 167, 175, 180, 185, 190, 195, 200, 300, 400, 500, ormore.

In some embodiments, relative gene expression, as compared to normalcells and/or tissues of the same organ, can be determined by measuringthe relative rates of transcription of RNA, such as by production ofcorresponding cDNAs and then analyzing the resulting DNA using probesdeveloped from the gene sequences as corresponding to a genetic marker.Thus, the levels of cDNA produced by use of reverse transcriptase withthe full RNA complement of a cell suspected of being cancerous producesa corresponding amount of cDNA that can then be amplified usingpolymerase chain reaction, or some other means, such as linearamplification, isothermal amplification, NASB, or rolling circleamplification, to determine the relative levels of resulting cDNA and,thereby, the relative levels of gene expression. General methods fordetermining gene expression product levels are known to the art and mayinclude but are not limited to one or more of the following: additionalcytological assays, assays for specific proteins or enzyme activities,assays for specific expression products including protein or RNA orspecific RNA splice variants, in situ hybridization, whole or partialgenome expression analysis, microarray hybridization assays, SAGE,enzyme linked immuno-absorbance assays, mass-spectrometry,immuno-histochemistry, blotting, microarray, RT-PCR, quantitative PCR,sequencing, RNA sequencing, DNA sequencing (e.g., sequencing of cDNAobtained from RNA); Next-Gen sequencing, nanopore sequencing,pyrosequencing, or Nanostring sequencing. Gene expression product levelsmay be normalized to an internal standard such as total mRNA or theexpression level of a particular gene including but not limited toglyceraldehyde 3-phosphate dehydrogenase, or tubulin.

Gene expression data generally comprises the measurement of the activity(or the expression) of a plurality of genes, to create a picture ofcellular function. Gene expression data can be used, for example, todistinguish between cells that are actively dividing, or to show how thecells react to a particular treatment. Microarray technology can be usedto measure the relative activity of previously identified target genesand other expressed sequences. Sequence based techniques, like serialanalysis of gene expression (SAGE, SuperSAGE) are also used forassaying, measuring or obtaining gene expression data. SuperSAGE isespecially accurate and can measure any active gene, not just apredefined set. In an RNA, mRNA or gene expression profiling microarray,the expression levels of thousands of genes can be simultaneouslymonitored to study the effects of certain treatments, diseases, anddevelopmental stages on gene expression.

In accordance with the foregoing, the expression level of a gene,marker, gene expression product, mRNA, pre-mRNA, or a combinationthereof may be determined using northern blotting and employing thesequences as identified herein to develop probes for this purpose. Suchprobes may be composed of DNA or RNA or synthetic nucleotides or acombination of these and may advantageously be comprised of a contiguousstretch of nucleotide residues matching, or complementary to, a sequencecorresponding to a genetic marker identified in FIG. 4. Such probes willmost usefully comprise a contiguous stretch of at least 15-200 residuesor more including 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 85, 90, 95, 100,110, 120, 130, 140, 150, 160, 175, or 200 nucleotides or more. Thus,where a single probe binds multiple times to the transcriptome ofexperimental cells, whereas binding of the same probe to a similaramount of transcriptome derived from the genome of control cells of thesame organ or tissue results in observably more or less binding, this isindicative of differential expression of a gene, marker, gene expressionproduct, mRNA, or pre-mRNA comprising, or corresponding to, sequencescorresponding to a genetic marker from which the probe sequence wasderived.

In some embodiments of the present invention, gene expression may bedetermined by microarray analysis using, for example, Affymetrix arrays,cDNA microarrays, oligonucleotide microarrays, spotted microarrays, orother microarray products from Biorad, Agilent, or Eppendorf.Microarrays provide particular advantages because they may contain alarge number of genes or alternative splice variants that may be assayedin a single experiment. In some cases, the microarray device may containthe entire human genome or transcriptome or a substantial fractionthereof allowing a comprehensive evaluation of gene expression patterns,genomic sequence, or alternative splicing. Markers may be found usingstandard molecular biology and microarray analysis techniques asdescribed in Sambrook Molecular Cloning a Laboratory Manual 2001 andBaldi, P., and Hatfield, W. G., DNA Microarrays and Gene Expression2002.

Microarray analysis generally begins with extracting and purifyingnucleic acid from a biological sample, (e.g. a biopsy or fine needleaspirate) using methods known to the art. For expression and alternativesplicing analysis it may be advantageous to extract and/or purify RNAfrom DNA. It may further be advantageous to extract and/or purify mRNAfrom other forms of RNA such as tRNA and rRNA. In some embodiments, RNAsamples with RIN ≤5.0 are typically not used for multi-gene microarrayanalysis, and may instead be used only for single-gene RT-PCR and/orTaqMan assays. Microarray, RT-PCR and TaqMan assays are standardmolecular techniques well known in the relevant art. TaqMan probe-basedassays are widely used in real-time PCR including gene expressionassays, DNA quantification and SNP genotyping.

Various kits can be used for the amplification of nucleic acid and probegeneration of the subject methods. In some embodiments, AmbionWT-expression kit can be used. Ambion WT-expression kit allowsamplification of total RNA directly without a separate ribosomal RNA(rRNA) depletion step. With the Ambion® WT Expression Kit, samples assmall as 50 ng of total RNA can be analyzed on Affymetrix® GeneChip®Human, Mouse, and Rat Exon and Gene 1.0 ST Arrays. In addition to thelower input RNA requirement and high concordance between the Affymetrix®method and TaqMan® real-time PCR data, the Ambion® WT Expression Kitprovides a significant increase in sensitivity. For example, a greaternumber of probe sets detected above background can be obtained at theexon level with the Ambion® WT Expression Kit as a result of anincreased signal-to-noise ratio. Ambion WT-expression kit may be used incombination with additional Affymetrix labeling kit.

In some embodiments, AmpTec Trinucleotide Nano mRNA Amplification kit(6299-A15) can be used in the subject methods. The ExpressArt®TRinucleotide mRNA amplification Nano kit is suitable for a wide range,from 1 ng to 700 ng of input total RNA. According to the amount of inputtotal RNA and the required yields of a RNA, it can be used for 1-round(input >300 ng total RNA) or 2-rounds (minimal input amount 1 ng totalRNA), with a RNA yields in the range of >10 μg. AmpTec's proprietaryTRinucleotide priming technology results in preferential amplificationof mRNAs (independent of the universal eukaryotic 3′-poly(A)-sequence),combined with selection against rRNAs. This kit can be used incombination with cDNA conversion kit and Affymetrix labeling kit.

In some embodiments, gene expression levels can be obtained or measuredin an individual without first obtaining a sample. For example, geneexpression levels may be determined in vivo, that is in the individual.Methods for determining gene expression levels in vivo are known to theart and include imaging techniques such as CAT, MRI; NMR; PET; andoptical, fluorescence, or biophotonic imaging of protein or RNA levelsusing antibodies or molecular beacons. Such methods are described in US2008/0044824, US 2008/0131892, herein incorporated by reference.Additional methods for in vivo molecular profiling are contemplated tobe within the scope of the present invention.

Provided herein are methods for determining whether an SMSM compound ora pharmaceutically acceptable salt thereof modulates the amount of one,two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcriptsor isoforms thereof) of one, two, three or more genes.

In one embodiment, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript, comprising: (a) contacting a cell withan SMSM compound or a pharmaceutically acceptable salt thereof, and (b)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof relative to the amount of the RNA transcript in the absence ofan SMSM compound or a pharmaceutically acceptable salt thereof or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of the RNA transcript. In someembodiments, provided herein is a method for determining whether an SMSMcompound or a pharmaceutically acceptable salt thereof modulates theamount of an RNA transcript (e.g., an mRNA transcript), comprising: (a)contacting a first cell with an SMSM compound or a pharmaceuticallyacceptable salt thereof, (b) contacting a second cell with a negativecontrol (e.g., a vehicle control, such as PBS or DMSO); and (c)determining the amount of the RNA transcript produced by the first celland the second cell; and (d) comparing the amount of the RNA transcriptproduced by the first cell to the amount of the RNA transcript expressedby the second cell, wherein an alteration in the amount of the RNAtranscript produced by the first cell relative to the amount of the RNAtranscript produced by the second cell indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript. In some embodiments, the contacting of the cell withthe compound occurs in cell culture. In other embodiments, thecontacting of the cell with the compound occurs in a subject, such as anon-human animal subject. In some embodiments, provided herein is amethod for determining whether an SMSM compound or a pharmaceuticallyacceptable salt thereof modulates the splicing of an RNA transcript(e.g., an mRNA transcript), comprising: (a) culturing a cell in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof; and (b) determining the amount of the two or more RNAtranscripts splice variants produced by the cell, wherein an alterationin the amount of the two or more RNA transcripts in the presence of thecompound relative to the amount of the two or more RNA transcriptssplice variants in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat an SMSM compound or a pharmaceutically acceptable salt thereofmodulates the splicing of the RNA transcript.

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe splicing of an RNA transcript (e.g., an mRNA transcript),comprising: (a) culturing a cell in the presence of an SMSM compound ora pharmaceutically acceptable salt thereof; (b) isolating two or moreRNA transcript splice variants from the cell after a certain period oftime; and (c) determining the amount of the two or more RNA transcriptsplice variants produced by the cell, wherein an alteration in theamount of the two or more RNA transcript in the presence of the compoundrelative to the amount of the two or more RNA transcript splice variantsin the absence of the compound or the presence of a negative control(e.g., a vehicle control such as PBS or DMSO) indicates that an SMSMcompound or a pharmaceutically acceptable salt thereof modulates thesplicing of the RNA transcript. In some embodiments, provided herein isa method for determining whether an SMSM compound or a pharmaceuticallyacceptable salt thereof modulates the splicing of an RNA transcript(e.g., an mRNA transcript), comprising (a) culturing a first cell in thepresence of an SMSM compound or a pharmaceutically acceptable saltthereof; (b) culturing a second cell in the presence of a negativecontrol (e.g., a vehicle control, such as PBS or DMSO); (c) isolatingtwo or more RNA transcript splice variants produced by the first celland isolating two or more RNA transcript splice variants produced by thesecond cell; (d) determining the amount of the two or more RNAtranscript splice variants produced by the first cell and the secondcell; and (e) comparing the amount of the two or more RNA transcriptsplice variants produced by the first cell to the amount of the two ormore RNA transcript splice variants produced by the second cell, whereinan alteration in the amount of the two or more RNA transcript splicevariants produced by the first cell relative to the amount of the two ormore RNA transcript splice variants produced by the second cellindicates that an SMSM compound or a pharmaceutically acceptable saltthereof modulates the splicing of the RNA transcript.

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript (e.g., an mRNA transcript), comprising:(a) contacting a cell-free system with an SMSM compound or apharmaceutically acceptable salt thereof, and (b) determining the amountof the RNA transcript produced by the cell-free system, wherein analteration in the amount of the RNA transcript in the presence of thecompound relative to the amount of the RNA transcript in the absence ofthe compound or the presence of a negative control (e.g., a vehiclecontrol such as PBS or DMSO) indicates that an SMSM compound or apharmaceutically acceptable salt thereof modulates the amount of the RNAtranscript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell-free system with anSMSM compound or a pharmaceutically acceptable salt thereof, (b)contacting a second cell-free system with a negative control (e.g., avehicle control, such as PBS or DMSO); and (c) determining the amount ofthe RNA transcript produced by the first cell-free system and the secondcell-free system; and (d) comparing the amount of the RNA transcriptproduced by the first cell-free system to the amount of the RNAtranscript expressed by the second cell-free system, wherein analteration in the amount of the RNA transcript produced by the firstcell-free system relative to the amount of the RNA transcript producedby the second cell-free system indicates that an SMSM compound or apharmaceutically acceptable salt thereof modulates the amount of the RNAtranscript.

In some embodiments, the cell-free system comprises purely syntheticRNA, synthetic or recombinant (purified) enzymes, and protein factors.In other embodiments, the cell-free system comprises RNA transcribedfrom a synthetic DNA template, synthetic or recombinant (purified)enzymes, and protein factors. In other embodiments, the cell-free systemcomprises purely synthetic RNA and nuclear extract. In otherembodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template and nuclear extract. In other embodiments, thecell-free system comprises purely synthetic RNA and whole cell extract.In other embodiments, the cell-free system comprises RNA transcribedfrom a synthetic DNA template and whole cell extract. In someembodiments, the cell-free system additionally comprises regulatory RNAs(e.g., microRNAs).

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe splicing of an RNA transcript (e.g., an mRNA transcript),comprising: (a) contacting a cell-free system with an SMSM compound or apharmaceutically acceptable salt thereof; and (b) determining the amountof two or more RNA transcript splice variants produced by the cell-freesystem, wherein an alteration in the amount of the two or more RNAtranscript splice variants in the presence of the compound relative tothe amount of the two or more RNA transcript splice variants in theabsence of the compound or the presence of a negative control (e.g., avehicle control such as PBS or DMSO) indicates that an SMSM compound ora pharmaceutically acceptable salt thereof modulates the splicing of theRNA transcript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the splicing of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell-free system with anSMSM compound or a pharmaceutically acceptable salt thereof; (b)contacting a second cell-free system with a negative control (e.g., avehicle control, such as PBS or DMSO); and (c) determining the amount oftwo or more RNA transcript splice variants produced by the firstcell-free system and the second cell-free system; and (d) comparing theamount of the two or more RNA transcript splice variants produced by thefirst cell-free system to the amount of the RNA transcript expressed bythe second cell-free system, wherein an alteration in the amount of thetwo or more RNA transcript splice variants produced by the firstcell-free system relative to the amount of the two or more RNAtranscript splice variants produced by the second cell-free systemindicates that an SMSM compound or a pharmaceutically acceptable saltthereof modulates the splicing of the RNA transcript. In someembodiments, the cell-free system comprises purely synthetic RNA,synthetic or recombinant (purified) enzymes, and protein factors. Inother embodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template, synthetic or recombinant (purified) enzymes, andprotein factors. In other embodiments, the cell-free system comprisespurely synthetic RNA and nuclear extract. In other embodiments, thecell-free system comprises RNA transcribed from a synthetic DNA templateand nuclear extract. In other embodiments, the cell-free systemcomprises purely synthetic RNA and whole cell extract. In otherembodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template and whole cell extract. In some embodiments, thecell-free system additionally comprises regulatory RNAs (e.g.,microRNAs).

In some embodiments, provided herein is a method for determining whetheran SMSM compound or a pharmaceutically acceptable salt thereof modulatesthe amount of an RNA transcript (e.g., an mRNA transcript), comprising:(a) culturing a cell in the presence of an SMSM compound or apharmaceutically acceptable salt thereof, (b) isolating the RNAtranscript from the cell after a certain period of time; and (c)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of the compound relative to the amount of the RNA transcript inthe absence of the compound or the presence of a negative control (e.g.,a vehicle control such as PBS or DMSO) indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript. In some embodiments, provided herein is a method fordetermining whether an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising (a) culturing a first cell in the presence of anSMSM compound or a pharmaceutically acceptable salt thereof, (b)culturing a second cell in the presence of a negative control (e.g., avehicle control, such as PBS or DMSO); (c) isolating the RNA transcriptproduced by the first cell and isolating the RNA transcript produced bythe second cell; (d) determining the amount of the RNA transcriptproduced by the first cell and the second cell; and (e) comparing theamount of the RNA transcript produced by the first cell to the amount ofthe RNA transcript produced by the second cell, wherein an alteration inthe amount of the RNA transcript produced by the first cell relative tothe amount of the RNA transcript produced by the second cell indicatesthat an SMSM compound or a pharmaceutically acceptable salt thereofmodulates the amount of the RNA transcript.

In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a primary cellfrom a subject. In some embodiments, the cell contacted or cultured withan SMSM compound or a pharmaceutically acceptable salt thereof is aprimary cell from a subject with a disease. In specific embodiments, thecell contacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is a primary cell from a subject with a diseaseassociated with an aberrant amount of an RNA transcript for a particulargene. In some specific embodiments, the cell contacted or cultured withan SMSM compound or a pharmaceutically acceptable salt thereof is aprimary cell from a subject with a disease associated with an aberrantamount of an isoform of a particular gene. In some embodiments, the cellcontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is a fibroblast, an immune cell, or a musclecell. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a diseasedcell.

In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is from a cellline. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a cell linederived from a subject with a disease. In some embodiments, the cellcontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is from a cell line known to have aberrant RNAtranscript levels for a particular gene. In specific embodiments, thecell contacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof is from a cell line derived from a subject witha disease known to have aberrant RNA transcript levels for a particulargene. In some embodiments, the cell contacted or cultured with an SMSMcompound or a pharmaceutically acceptable salt thereof is a diseasedcell line. In some specific embodiments, the cell contacted or culturedwith an SMSM compound or a pharmaceutically acceptable salt thereof isfrom a cell line derived from a subject with a disease known to have anaberrant amount of an RNA isoform and/or protein isoform of a particulargene. Non-limiting examples of cell lines include 293, 3T3, 4T1, 721,9L, A2780, A172, A20, A253, A431, A-549, A-673, ALC, B 16, B35, BCP-1,BEAS—2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3 h-10T1/2,C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML Tl, CMT, CRL7030,CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69,HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, Hs578T,HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22,KG1, KYOl, LNCap, Ma-Mel, MC-38, MCF-7, MCF-IOA, MDA-MB-231, MDA-MB-468,MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69,N1H-3T3, NALM-1, NSO, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL,RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, S1Ha, SKBR3, SKOV-3, T2, T-47D,T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63,YAC-1, and YAR cells. In one embodiment, the cells are from a patient.

In some embodiments, a dose-response assay is performed. In oneembodiment, the dose response assay comprises: (a) contacting a cellwith a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof; (b) determining the amount of the RNAtranscript produced by the cell, wherein an alteration in the amount ofthe RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that an SMSM compound or a pharmaceutically acceptablesalt thereof modulates the amount of the RNA transcript; (c) repeatingsteps (a) and (b), wherein the only experimental variable changed is theconcentration of the compound or a form thereof; and (d) comparing theamount of the RNA transcript produced at the different concentrations ofthe compound or a form thereof. In some embodiments, the dose responseassay comprises: (a) culturing a cell in the presence of an SMSMcompound or a pharmaceutically acceptable salt thereof, (b) isolatingthe RNA transcript from the cell after a certain period of time; (c)determining the amount of the RNA transcript produced by the cell,wherein an alteration in the amount of the RNA transcript in thepresence of the compound relative to the amount of the RNA transcript inthe absence of the compound or the presence of a negative control (e.g.,a vehicle control such as PBS or DMSO) indicates that an SMSM compoundor a pharmaceutically acceptable salt thereof modulates the amount ofthe RNA transcript; (d) repeating steps (a), (b), and (c), wherein theonly experimental variable changed is the concentration of the compoundor a form thereof; and (e) comparing the amount of the RNA transcriptproduced at the different concentrations of the compound or a formthereof. In some embodiments, the dose-response assay comprises: (a)contacting each well of a microtiter plate containing cells with adifferent concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof; (b) determining the amount of an RNA transcriptproduced by cells in each well; and (c) assessing the change of theamount of the RNA transcript at the different concentrations of thecompound or form thereof.

In some embodiments described herein, the cell is contacted or culturedwith an SMSM compound or a pharmaceutically acceptable salt thereof, ora tissue sample is contacted with an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a negative control for a period of 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72hours or more. In other embodiments described herein, the cell iscontacted or cultured with an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a tissue sample is contacted with an SMSMcompound or a pharmaceutically acceptable salt thereof, or a negativecontrol for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24to 48 hours, 48 to 72 hours.

In some embodiments described herein, the cell is contacted or culturedwith a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof, or a tissue sample is contacted with aconcentration of an SMSM compound or a pharmaceutically acceptable saltthereof, wherein the concentration is 0.01 M, 0.05 μM, 1 μM, 2 μM, 5 μM,10 μM, 15 μM, 20 μM, 25 M, 50 M, 75 RM, 100 RM, or 150 RM.

In other embodiments described herein, the cell is contacted or culturedwith concentration of an SMSM compound or a pharmaceutically acceptablesalt thereof, or a tissue sample is contacted with a concentration of anSMSM compound or a pharmaceutically acceptable salt thereof, wherein theconcentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 M,450 μM, 500 μM, 550 μM 600 μM, 650 μM, 700 M, 750 μM, 800 μM, 850 μM,900 μM, 950 μM or 1 mM. In some embodiments described herein, the cellis contacted or cultured with concentration of an SMSM compound or apharmaceutically acceptable salt thereof, or a tissue sample iscontacted with a concentration of an SMSM compound or a pharmaceuticallyacceptable salt thereof, wherein the concentration is 5 nM, 10 nM, 20nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In someembodiments described herein, the cell is contacted or cultured withconcentration of an SMSM compound or a pharmaceutically acceptable saltthereof, or a tissue sample is contacted with a concentration of an SMSMcompound or a pharmaceutically acceptable salt thereof, wherein theconcentration is between 0.01 μM to 0.1 M, 0.1 μM to 1 RM, 1 M to 50 M,50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nMto 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.

Techniques known to one skilled in the art may be used to determine theamount of an RNA transcript. In some embodiments, the amount of one,two, three or more RNA transcripts is measured using deep sequencing,such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS),ION TORRENT™ RNA next generation sequencing, 454™ pyrosequencing, orSequencing by Oligo Ligation Detection (SOLID™). In other embodiments,the amount of multiple RNA transcripts is measured using an exon array,such as the GENECHIP® human exon array. In some embodiments, the amountof one, two, three or more RNA transcripts is determined by RT-PCR. Inother embodiments, the amount of one, two, three or more RNA transcriptsis measured by RT-qPCR. Techniques for conducting these assays are knownto one skilled in the art.

In some embodiments, a statistical analysis or other analysis isperformed on data from the assay utilized to measure an RNA transcript.In some embodiments, a student t-test statistical analysis is performedon data from the assay utilized to measure an RNA transcript todetermine those RNA transcripts that have an alternation in amount inthe presence of the compound relative to the amount in the absence ofthe compound or presence of a negative control. In specific embodiments,the student t-test value of those RNA transcripts with the alternationis 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. In some specific embodiments,p value of those RNA transcripts with the alternation is 10%, 5%, 4%,3%, 2%, 1%, 0.5% or 0.1%. In certain specific embodiments, the studentt-test and p values of those RNA transcripts with the alteration are10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%or 0.1%), respectively.

In some embodiments, a further analysis is performed to determine how anSMSM compound or a pharmaceutically acceptable salt thereof is changingthe amount of an RNA transcript. In specific embodiments, a furtheranalysis is performed to determine if an alternation in the amount of anRNA transcript in the presence of an SMSM compound or a pharmaceuticallyacceptable salt thereof relative the amount of the RNA transcript in theabsence of the compound or a form thereof, or the presence of a negativecontrol is due to changes in transcription, splicing, and/or stabilityof the RNA transcript. Techniques known to one skilled in the art may beused to determine whether an SMSM compound or a pharmaceuticallyacceptable salt thereof changes, e.g., the transcription, splicingand/or stability of an RNA transcript.

In some embodiments, the stability of one or more RNA transcripts isdetermined by serial analysis of gene expression (SAGE), differentialdisplay analysis (DD), RNA arbitrarily primer (RAP)-PCR, restrictionendonuclease-lytic analysis of differentially expressed sequences(READS), amplified restriction fragment-length polymorphism (ALFP),total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-densitycDNA filter hybridization analysis (HDFCA), suppression subtractivehybridization (SSH), differential screening (DS), cDNA arrays,oligonucleotide chips, or tissue microarrays. In other embodiments, thestability of one or more RNA transcripts is determined by Northernblots, RNase protection, or slot blots.

In some embodiments, the transcription in a cell or tissue sample isinhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) thecell or the tissue sample is contacted or cultured with an inhibitor oftranscription, such as a-amanitin, DRB, flavopiridol, triptolide, oractinomycin-D. In other embodiments, the transcription in a cell ortissue sample is inhibited with an inhibitor of transcription, such asα-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while thecell or tissue sample is contacted or cultured with an SMSM compound ora pharmaceutically acceptable salt thereof.

In some embodiments, the level of transcription of one or more RNAtranscripts is determined by nuclear run-on assay or an in vitrotranscription initiation and elongation assay. In some embodiments, thedetection of transcription is based on measuring radioactivity orfluorescence. In some embodiments, a PCR-based amplification step isused.

In some embodiments, the amount of alternatively spliced forms of theRNA transcripts of a particular gene are measured to see if there is analteration in the amount of one, two or more alternatively spliced formsof the RNA transcripts of the gene. In some embodiments, the amount ofan isoform encoded by a particular gene is measured to see if there isan alteration in the amount of the isoform. In some embodiments, thelevels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, ornorthern blotting. In other embodiments, sequence-specific techniquesmay be used to detect the levels of an individual splice form. In someembodiments, splicing is measured in vitro using nuclear extracts. Insome embodiments, detection is based on measuring radioactivity orfluorescence. Techniques known to one skilled in the art may be used tomeasure alterations in the amount of alternatively spliced forms of anRNA transcript of a gene and alterations in the amount of an isoformencoded by a gene.

Biological Samples

A sample, e.g., a biological sample can be taken from a subject andexamined to determine whether the subject produces mRNA that is subjectto alternative splicing. A biological sample can comprise a plurality ofbiological samples. The plurality of biological samples can contain twoor more biological samples; for examples, about 2-1000, 2-500, 2-250,2-100, 2-75, 2-50, 2-25, 2-10, 10-1000, 10-500, 10-250, 10-100, 10-75,10-50, 10-25, 25-1000, 25-500, 25-250, 25-100, 25-75, 25-50, 50-1000,50-500, 50-250, 50-100, 50-75, 60-70, 100-1000, 100-500, 100-250,250-1000, 250-500, 500-1000, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100,110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240,250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650,700, 750, 800, 850, 900, 950, 1000, or more biological samples. Thebiological samples can be obtained from a plurality of subjects, givinga plurality of sets of a plurality of samples. The biological samplescan be obtained from about 2 to about 1000 subjects, or more; forexample, about 2-1000, 2-500, 2-250, 2-100, 2-50, 2-25, 2-20, 2-10,10-1000, 10-500, 10-250, 10-100, 10-50, 10-25, 10-20, 15-20, 25-1000,25-500, 25-250, 25-100, 25-50, 50-1000, 50-500, 50-250, 50-100,100-1000, 100-500, 100-250, 250-1000, 250-500, 500-1000, or at least 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 68, 70, 75, 80, 85, 90, 95,100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230,240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600,650, 700, 750, 800, 850, 900, 950, to 1000 or more subjects.

The biological samples can be obtained from human subjects. Thebiological samples can be obtained from human subjects at differentages. The human subject can be prenatal (e.g., a fetus), a child (e.g.,a neonate, an infant, a toddler, a preadolescent), an adolescent, apubescent, or an adult (e.g., an early adult, a middle aged adult, asenior citizen). The human subject can be between about 0 months andabout 120 years old, or older. The human subject can be between about 0and about 12 months old; for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 months old. The human subject can be between about 0 and12 years old; for example, between about 0 and 30 days old; betweenabout 1 month and 12 months old; between about 1 year and 3 years old;between about 4 years and 5 years old; between about 4 years and 12years old; about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years old. Thehuman subject can be between about 13 years and 19 years old; forexample, about 13, 14, 15, 16, 17, 18, or 19 years old. The humansubject can be between about 20 and about 39 year old; for example,about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, or 39 years old. The human subject can be between about 40to about 59 years old; for example, about 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years old. Thehuman subject can be greater than 59 years old; for example, about 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, or 120 years old. The humansubjects can include living subjects or deceased subjects. The humansubjects can include male subjects and/or female subjects.

Biological samples can be obtained from any suitable source that allowsdetermination of expression levels of genes, e.g., from cells, tissues,bodily fluids or secretions, or a gene expression product derivedtherefrom (e.g., nucleic acids, such as DNA or RNA; polypeptides, suchas protein or protein fragments). The nature of the biological samplecan depend upon the nature of the subject. If a biological sample isfrom a subject that is a unicellular organism or a multicellularorganism with undifferentiated tissue, the biological sample cancomprise cells, such as a sample of a cell culture, an excision of theorganism, or the entire organism. If a biological sample is from amulticellular organism, the biological sample can be a tissue sample, afluid sample, or a secretion.

The biological samples can be obtained from different tissues. The termtissue is meant to include ensembles of cells that are of a commondevelopmental origin and have similar or identical function. The termtissue is also meant to encompass organs, which can be a functionalgrouping and organization of cells that can have different origins. Thebiological sample can be obtained from any tissue. Suitable tissues froma plant can include, but are not limited to, epidermal tissue such asthe outer surface of leaves; vascular tissue such as the xylem andphloem, and ground tissue. Suitable plant tissues can also includeleaves, roots, root tips, stems, flowers, seeds, cones, shoots, stobili,pollen, or a portion or combination thereof.

The biological samples can be obtained from different tissue samplesfrom one or more humans or non-human animals. Suitable tissues caninclude connective tissues, muscle tissues, nervous tissues, epithelialtissues or a portion or combination thereof. Suitable tissues can alsoinclude all or a portion of a lung, a heart, a blood vessel (e.g.,artery, vein, capillary), a salivary gland, a esophagus, a stomach, aliver, a gallbladder, a pancreas, a colon, a rectum, an anus, ahypothalamus, a pituitary gland, a pineal gland, a thyroid, aparathyroid, an adrenal gland, a kidney, a ureter, a bladder, a urethra,a lymph node, a tonsil, an adenoid, a thymus, a spleen, skin, muscle, abrain, a spinal cord, a nerve, an ovary, a fallopian tube, a uterus,vaginal tissue, a mammary gland, a testicle, a vas deferens, a seminalvesicle, a prostate, penile tissue, a pharynx, a larynx, a trachea, abronchi, a diaphragm, bone marrow, a hair follicle, or a combinationthereof. A biological sample from a human or non-human animal can alsoinclude a bodily fluid, secretion, or excretion; for example, abiological sample can be a sample of aqueous humour, vitreous humour,bile, blood, blood serum, breast milk, cerebrospinal fluid, endolymph,perilymph, female ejaculate, amniotic fluid, gastric juice, menses,mucus, peritoneal fluid, pleural fluid, saliva, sebum, semen, sweat,tears, vaginal secretion, vomit, urine, feces, or a combination thereof.The biological sample can be from healthy tissue, diseased tissue,tissue suspected of being diseased, or a combination thereof.

In some embodiments, the biological sample is a fluid sample, forexample a sample of blood, serum, sputum, urine, semen, or otherbiological fluid. In certain embodiments the sample is a blood sample.In some embodiments the biological sample is a tissue sample, such as atissue sample taken to determine the presence or absence of disease inthe tissue. In certain embodiments the sample is a sample of thyroidtissue.

The biological samples can be obtained from subjects in different stagesof disease progression or different conditions. Different stages ofdisease progression or different conditions can include healthy, at theonset of primary symptom, at the onset of secondary symptom, at theonset of tertiary symptom, during the course of primary symptom, duringthe course of secondary symptom, during the course of tertiary symptom,at the end of the primary symptom, at the end of the secondary symptom,at the end of tertiary symptom, after the end of the primary symptom,after the end of the secondary symptom, after the end of the tertiarysymptom, or a combination thereof. Different stages of diseaseprogression can be a period of time after being diagnosed or suspectedto have a disease; for example, at least about, or at least, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23 or24 hours; 1, 2,3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days; 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks; 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11 or 12 months; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49or 50 years after being diagnosed or suspected to have a disease.Different stages of disease progression or different conditions caninclude before, during or after an action or state; for example,treatment with drugs, treatment with a surgery, treatment with aprocedure, performance of a standard of care procedure, resting,sleeping, eating, fasting, walking, running, performing a cognitivetask, sexual activity, thinking, jumping, urinating, relaxing, beingimmobilized, being emotionally traumatized, being shock, and the like.

The methods of the present disclosure provide for analysis of abiological sample from a subject or a set of subjects. The subject(s)may be, e.g., any animal (e.g., a mammal), including but not limited tohumans, non-human primates, rodents, dogs, cats, pigs, fish, and thelike. The present methods and compositions can apply to biologicalsamples from humans, as described herein.

A biological sample can be obtained by methods known in the art such asthe biopsy methods provided herein, swabbing, scraping, phlebotomy, orany other suitable method. The biological sample can be obtained,stored, or transported using components of a kit of the presentdisclosure. In some cases, multiple biological samples, such as multiplethyroid samples, can be obtained for analysis, characterization, ordiagnosis according to the methods of the present disclosure. In somecases, multiple biological samples, such as one or more samples from onetissue type (e.g., thyroid) and one or more samples from another tissuetype (e.g., buccal) can be obtained for diagnosis or characterization bythe methods of the present disclosure. In some cases, multiple samples,such as one or more samples from one tissue type (e.g., thyroid) and oneor more samples from another tissue (e.g., buccal) can be obtained atthe same or different times. In some cases, the samples obtained atdifferent times are stored and/or analyzed by different methods. Forexample, a sample can be obtained and analyzed by cytological analysis(e.g., using routine staining). In some cases, a further sample can beobtained from a subject based on the results of a cytological analysis.The diagnosis of cancer or other condition can include an examination ofa subject by a physician, nurse or other medical professional. Theexamination can be part of a routine examination, or the examination canbe due to a specific complaint including, but not limited to, one of thefollowing: pain, illness, anticipation of illness, presence of asuspicious lump or mass, a disease, or a condition. The subject may ormay not be aware of the disease or condition. The medical professionalcan obtain a biological sample for testing. In some cases the medicalprofessional can refer the subject to a testing center or laboratory forsubmission of the biological sample. The methods of obtaining providedherein include methods of biopsy including fine needle aspiration, coreneedle biopsy, vacuum assisted biopsy, incisional biopsy, excisionalbiopsy, punch biopsy, shave biopsy or skin biopsy. In some cases, themethods and compositions provided herein are applied to data only frombiological samples obtained by FNA. In some cases, the methods andcompositions provided herein are applied to data only from biologicalsamples obtained by FNA or surgical biopsy. In some cases, the methodsand compositions provided herein are applied to data only frombiological samples obtained by surgical biopsy. A biological sample canbe obtained by non-invasive methods, such methods including, but notlimited to: scraping of the skin or cervix, swabbing of the cheek,saliva collection, urine collection, feces collection, collection ofmenses, tears, or semen. The biological sample can be obtained by aninvasive procedure, such procedures including, but not limited to:biopsy, alveolar or pulmonary lavage, needle aspiration, or phlebotomy.The method of biopsy can further include incisional biopsy, excisionalbiopsy, punch biopsy, shave biopsy, or skin biopsy. The method of needleaspiration can further include fine needle aspiration, core needlebiopsy, vacuum assisted biopsy, or large core biopsy. Multiplebiological samples can be obtained by the methods herein to ensure asufficient amount of biological material. Methods of obtaining suitablesamples of thyroid are known in the art and are further described in theATA Guidelines for thyroid nodule management (Cooper et al. Thyroid Vol.16 No. 2 2006), herein incorporated by reference in its entirety.Generic methods for obtaining biological samples are also known in theart and further described in for example Ramzy, Ibrahim ClinicalCytopathology and Aspiration Biopsy 2001 which is herein incorporated byreference in its entirety. The biological sample can be a fine needleaspirate of a thyroid nodule or a suspected thyroid tumor. The fineneedle aspirate sampling procedure can be guided by the use of anultrasound, X-ray, or other imaging device.

In some cases, the subject can be referred to a specialist such as anoncologist, surgeon, or endocrinologist for further diagnosis. Thespecialist can likewise obtain a biological sample for testing or referthe individual to a testing center or laboratory for submission of thebiological sample. In any case, the biological sample can be obtained bya physician, nurse, or other medical professional such as a medicaltechnician, endocrinologist, cytologist, phlebotomist, radiologist, or apulmonologist. The medical professional can indicate the appropriatetest or assay to perform on the sample, or the molecular profilingbusiness of the present disclosure can consult on which assays or testsare most appropriately indicated. The molecular profiling business canbill the individual or medical or insurance provider thereof forconsulting work, for sample acquisition and or storage, for materials,or for all products and services rendered.

A medical professional need not be involved in the initial diagnosis orsample acquisition. An individual can alternatively obtain a samplethrough the use of an over the counter kit. The kit can contain a meansfor obtaining said sample as described herein, a means for storing thesample for inspection, and instructions for proper use of the kit. Insome cases, molecular profiling services are included in the price forpurchase of the kit. In other cases, the molecular profiling servicesare billed separately.

A biological sample suitable for use by the molecular profiling businesscan be any material containing tissues, cells, nucleic acids, genes,gene fragments, expression products, gene expression products, and/orgene expression product fragments of an individual to be tested. Methodsfor determining sample suitability and/or adequacy are provided. Thebiological sample can include, but is not limited to, tissue, cells,and/or biological material from cells or derived from cells of anindividual. The sample can be a heterogeneous or homogeneous populationof cells or tissues. The biological sample can be obtained using anymethod known to the art that can provide a sample suitable for theanalytical methods described herein.

Obtaining a biological sample can be aided by the use of a kit. A kitcan be provided containing materials for obtaining, storing, and/orshipping biological samples. The kit can contain, for example, materialsand/or instruments for the collection of the biological sample (e.g.,sterile swabs, sterile cotton, disinfectant, needles, syringes,scalpels, anesthetic swabs, knives, curette blade, liquid nitrogen,etc.). The kit can contain, for example, materials and/or instrumentsfor the storage and/or preservation of biological samples (e.g.,containers; materials for temperature control such as ice, ice packs,cold packs, dry ice, liquid nitrogen; chemical preservatives or bufferssuch as formaldehyde, formalin, paraformaldehyde, glutaraldehyde,alcohols such as ethanol or methanol, acetone, acetic acid, HOPEfixative (Hepes-glutamic acid buffer-mediated organic solvent protectioneffect), heparin, saline, phosphate buffered saline, TAPS, bicine, Tris,tricine, TAPSO, HEPES, TES, MOPS, PIPES, cadodylate, SSC, MES, phosphatebuffer; protease inhibitors such as aprotinin, bestatin, calpaininhibitor I and II, chymostatin, E-64, leupeptin, alpha-2-macroglobulin,pefabloc SC, pepstatin, phenylmethanesufonyl fluoride, trypsininhibitors; DNAse inhibitors such as 2-mercaptoethanol,2-nitro-5-thicyanobenzoic acid, calcium, EGTA, EDTA, sodium dodecylsulfate, iodoacetate, etc.; RNAse inhibitors such as ribonucleaseinhibitor protein; double-distilled water; DEPC (diethyprocarbonate)treated water, etc.). The kit can contain instructions for use. The kitcan be provided as, or contain, a suitable container for shipping. Theshipping container can be an insulated container. The shipping containercan be self-addressed to a collection agent (e.g., laboratory, medicalcenter, genetic testing company, etc.). The kit can be provided to asubject for home use or use by a medical professional. Alternatively,the kit can be provided directly to a medical professional.

One or more biological samples can be obtained from a given subject. Insome cases, between about 1 and about 50 biological samples are obtainedfrom the given subject; for example, about 1-50, 1-40, 1-30, 1-25, 1-20,1-15, 1-10, 1-7, 1-5, 5-50, 5-40, 5-30, 5-25, 5-15, 5-10, 10-50, 10-40,10-25, 10-20, 25-50, 25-40, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, or 50 biological samples can be obtained from the givensubject. Multiple biological samples from the given subject can beobtained from the same source (e.g., the same tissue), e.g., multipleblood samples, or multiple tissue samples, or from multiple sources(e.g., multiple tissues). Multiple biological samples from the givensubject can be obtained at the same time or at different times. Multiplebiological samples from the given subject can be obtained at the samecondition or different condition. Multiple biological samples from thegiven subject can be obtained at the same disease progression ordifferent disease progression of the subject. If multiple biologicalsamples are collected from the same source (e.g., the same tissue) fromthe particular subject, the samples can be combined into a singlesample. Combining samples in this way can ensure that enough material isobtained for testing and/or analysis.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

Example 1:2-(6-(cyclopropyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of 2,2,6,6-tetramethylpiperidin-4-amine (2.1 g, 14.1 mmol),3,6-dichloropyridazine (2 g, 12.8 mmol) and diisopropylethylamine (3.6g, 28.2 mmol) in 50 mL of n-butyl alcohol was stirred at 120° C. for 4h. The mixture was concentrated and ethyl acetate (60 mL) was added. Theresulting mixture was washed with 10 mL of H₂O, concentrated andtriturated in ethyl acetate/petroleum ether which gave 2.3 g of6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as whitesolid (67% yield). LCMS: m/z 269.2 [M+H]⁺; t_(R)=1.46 min.

Step 2: Synthesis of6-chloro-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (400 mg,1.5 mmol), cyclopropylboronic acid (387 mg, 4.5 mmol), Cu(OAc)₂ (273 mg,1.5 mmol), Na₂CO₃ (318 mg, 3 mmol) and triethylamine (303 mg, 3 mmol) in10 mL of 1,2-dichloroethane was stirred at room temperature for 16 h.The mixture was filtered, concentrated and purified by silica gel column(methanol/dichloromethane=0-20%) which gave 210 mg of6-chloro-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas black solid (34% yield). LCMS: m/z 309.2 [M+H]⁺; t_(R)=1.77 min.

Step 3: Synthesis of6-(4-chloro-2-methoxyphenyl)-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of6-chloro-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(160 mg, 0.52 mmol), 4-chloro-2-methoxyphenylboronic acid (106 mg, 0.57mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42mg, 0.05 mmol) and K₂CO₃ (144 mg, 1.04 mmol) in 3 mL of 1,4-dioxane and0.3 mL of water was degassed and stirred at 105° C. for 8 h undernitrogen atmosphere. The mixture was then concentrated and purified bysilica gel chromatography (0-20% methanol/dichloromethane) which gave150 mg of6-(4-chloro-2-methoxyphenyl)-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas black solid (53% yield). LCMS: m/z 415.1 [M+H]⁺; t_(R)=1.51 min.

Step 4: Synthesis ofN-cyclopropyl-6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of6-(4-chloro-2-methoxyphenyl)-N-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(110 mg, 0.27 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.4mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22mg, 0.03 mmol) and K₂CO₃ (73 mg, 0.53 mmol) in 4 mL of 1,4-dioxane and0.4 mL of water was purged with nitrogen and sealed. The mixture wasstirred at 130° C. under microwave irradiation for 2 h, concentrated andpurified by silica gel chromatography (0-20% MeOH/CH₂Cl₂) which gave 100mg ofN-cyclopropyl-6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas white solid (25% yield). LCMS: m z 447.3 [M+H]⁺; t_(R)=1.78 min.

Step 5: Synthesis of Title Compound,2-(6-(cyclopropyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A mixture ofN-cyclopropyl-6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(80 mg, 0.18 mmol) and sodium ethane thiolate (30 mg, 0.36 mmol) wasdissolved in N-Methyl-2-pyrrolidone (2 mL). The mixture was stirred at185° C. for 8 h. After cooling to room temperature, the mixture waspurified by reverse HPLC which gave 33 mg of2-(6-(cyclopropyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas yellow solid (34% yield).

Example 2: Synthesis of2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of tert-butyl(1R,3S,5S)-3-((6-chloropyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3S,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 1.77mmol), 3,6-dichloropyridazine (489 mg, 3.28 mmol) and DIPEA (652 mg, 5.1mmol) in 4 mL of DMSO was stirred at 120° C. for 18 h. After cooling toroom temperature, the mixture was quenched with 10 mL of water,extracted with EtOAc (20 mL×3). The combined organic solvents werewashed with water (10 mL), concentrated and purified by silica gelcolumn (5-80% EtOAc/petroleum ether) which gave 320 mg of tert-butyl(1R,3S,5S)-3-((6-chloropyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (53% yield). LCMS: m/z 339.2 [M+H]⁺; t_(R)=1.41 min.

Step 2: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (89 mg, 2.23 mmol, 60% in mineral oil) was added to astirred solution tert-butyl(1R,3S,5S)-3-((6-chloropyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(300 mg, 0.89 mmol) in 4 mL of DMF at 0° C. After stirring at 0° C. for40 min, Methyl Iodide (253 mg, 1.78 mmol) was added. The mixture wasthen allowed to warm up to room temperature and stirred for 2 h. Themixture was quenched with water (10 mL), extracted with EtOAc (30 mL×3),concentrated and purified by silica gel column (5-60% EtOAc/petroleumether) which gave 300 mg tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (96% yield). LCMS: m/z 353.0 [M+H]⁺; t_(R)=1.43 min.

Step 3: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-methoxyphenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(300 mg, 0.85 mmol), 4-chloro-2-methoxyphenylboronic acid (158 mg, 0.85mmol), Pd(dppf)Cl₂ (78 mg, 0.1 mmol) and K₂CO₃ (265 mg, 1.92 mmol) in 4mL of 1,4-dioxane and 0.4 mL of water was degassed and stirred at 105°C. for 6 h under nitrogen atmosphere. The mixture was then concentratedand purified by silica gel chromatography (5-60% EtOAc/petroleum ether)which gave 130 mg of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-methoxyphenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (34% yield). LCMS: m/z 459.1 [M+H]⁺; t_(R)=1.64 min.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-methoxyphenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(130 mg, 0.28 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.34mmol), Pd(dppf)Cl₂ (20 mg, 0.028 mmol) and K₂CO₃ (77 mg, 0.56 mmol) in 2mL of 1,4-dioxane and 0.4 mL of water was purged with nitrogen andsealed. The mixture was stirred at 130° C. under MW for 2 h,concentrated and purified by silica gel chromatography (0-50%MeOH/CH₂Cl₂) which gave 120 mg of tert-butyl(1R,3s,5S)-3-((6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (87% yield). LCMS: m/z 491.3 [M+H]⁺; t_(R)=1.98 min.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(120 mg, 0.24 mmol) and EtSNa (41 mg, 0.48 mmol) was dissolved in NMP (2mL). The mixture was stirred at 180° C. for 6 h. After cooling to roomtemperature, the mixture was purified by reverse HPLC (NH₄)₂CO₃ whichgave 70 mg of tert-butyl(1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (61% yield). LCMS: m/z 477.2 [M+H]⁺; t_(R)=1.58 min.

Step 6: Synthesis of Title Compound:2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A 2 ml solution of 4 N Hydrogen Chloride in dioxane was added to asolution of tert-butyl(1R,3s,5S)-3-((6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(70 mg, 0.15 mmol) in 1 mL of CH₂C2 at room temperature. After stirringat room temperature for 1 h, the mixture was concentrated, neutralizedwith ammonium hydroxide and purified by prep-HPLC (NH₄HCO₃) which gave36 mg of2-(6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas yellow solid (45% yield).

Example 3: Synthesis of2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.5 g, 10.42mmol), 3,6-dichloropyridazine (2.02 g, 13.55 mmol) and DIPEA (2.96 g,22.92 mmol) in 50 mL of DMSO was stirred at 120° C. for 6 h. The mixturewas cooled to room temperature, quenched with H₂O and extracted withethyl acetate (160 mL×3). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. After removal of solvent, the crude product was purified bysilica gel column (50% EtOAc/petroleum ether) which gave 2.3 g oftert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylateas yellow solid (yield: 63%). LCMS: m/z 353.2 [M+H]⁺; t_(R)=1.93 min.

Step 2: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

Sodium hydride (784 mg, 19.60 mmol, 60% in mineral oil) was added to astirred solution of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate(2.3 g, 6.54 mmol) in 40 mL of DMF at 0° C. After stirring for 20 min at0° C., CH₃I (1.9 g, 13.08 mmol) was added. The mixture was then stirredat room temperature for 1 h, quenched with H₂O and extracted with EtOAc(80 mL×3). The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄, concentrated under reduced pressure and purifiedby silica gel column (50% EtOAc/petroleum ether) which gave 2.0 g oftert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylateas yellow solid (84% yield). LCMS: m/z 367.2 [M+H]⁺; t_(R)=2.11 min.

Step 3: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene

Bromomethyl methyl ether (1.25 g, 10 mmol) was added to a stirredsolution of 2-bromo-5-iodophenol (1.5 g, 5 mmol) and K₂CO₃ (1.38 g, 10mmol) in 20 mL of DMF at 0° C. The mixture was then stirred at roomtemperature for 16 h, quenched with 20 mL of H₂O and extracted withEtOAc (20 mL×3). The combined organic solvents were dried over anhydrousNa₂SO₄, concentrated and purified by silica gel column (0-5%EtOAc/petroleum ether) which gave 1.45 g of1-bromo-4-iodo-2-(methoxymethoxy)benzene as colorless liquid (79%yield). LCMS: t_(R)=1.50 min.

Step 4: Synthesis of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (3.3 g, 9.6 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.67 g, 9.6 mmol), Pd(dppf)Cl₂ (866 mg, 1 mmol) and K₂CO₃ (2.66 g, 19.3mmol) in 40 mL of dioxane and 4 mL of H₂O was degassed and stirred at105° C. for 8 h. After cooling to room temperature, the mixture wasextracted with EtOAc (30 mL×3). The combined organic solvents wereconcentrated and purified by silica gel column (10-50% EtOAc/petroleumether) which gave 2.5 g of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (69% yield). LCMS: m/z 367.1 [M+H]⁺; t_(R)=2.03 min.

Step 5: Synthesis of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.5 g, 4.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.1 g, 8.2mmol), Pd(dppf)Cl₂ (369 mg, 0.41 mmol) and KOAc (804 mg, 8.2 mmol) in 20mL of dioxane was degassed and stirred at 105° C. for 8 h. The mixturewas filtered, concentrated and purified by silica gel column which gave0.81 g of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (48% yield). LCMS: m/z 415.3 [M+H]⁺; t_(R)=2.10 min.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate(1.7 g, 4.64 mmol),4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2.5 g, 6.04 mmol), Pd(dppf)Cl₂ (339 mg, 0.46 mmol) and K₂CO₃ (1.28 g,9.28 mmol) in 40 mL of 1,4-dioxane and 8 mL of water was degassed andstirred at 105° C. for 2 h under nitrogen atmosphere. The mixture wasthen concentrated and purified by silica gel chromatography (5-60%EtOAc/petroleum ether) which gave 2.2 g of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylateas pale yellow solid (77% yield). LCMS(A039): m/z 619.3 [M+H]⁺;t_(R)=2.17 min.

Step 7: Synthesis of Title Compound:2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A 10 mL solution of 4N HCl in dioxane was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate(2.2 g, 3.56 mmol) in 4 mL of CH₂C2. The mixture was stirred at roomtemperature for 2 h, concentrated under reduced pressure, neutralizedwith NH₃/MeOH and purified by prep-HPLC which gave 900 mg of2-(6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas a yellow solid (65% yield).

Example 4: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

A solution of potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O wasadded to a stirred solution of 3-oxopentanedioic acid (120 g, 822 mmol)and hexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O at 0° C.Ammonium chloride (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1 g, 515mmol) in 667 mL of H₂O was then added with stirring. The pH of theresulting solution was adjusted to ˜9 using 1 N NaOH aqueous solution.The mixture was stirred at room temperature for about 72 h during whichtime the pH was maintained at approximately 9 by using additional 1 NNaOH. The mixture was extracted with CH₂C2(1 L X 5). The combinedorganic solvents were dried over anhydrous Na₂SO₄, concentrated andpurified by silica gel chromatography (0-25% MeOH/CH₂Cl₂) which gave16.7 g of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25%yield). LCMS(039): m/z 154.2 [M+H]⁺; t_(R)=1.20 min; purity: 85%.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) which gave 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS(042): m/z 198.1 [M-55]⁺; t_(R)=1.40 min;purity: 100%.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and sodiumacetate (10.8 g, 132 mmol) in 250 mL of ethanol was stirred at 70° C.for 4 h. The mixture was concentrated. 200 mL of EtOAc and 60 mL of H₂Owas added. The organic phase was separated, washed with brine (50 mL),dried over anhydrous Na₂SO₄, concentrated to give 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS(039): m/z 269.2 [M+H]⁺; t_(R)=1.92 min; purity: 100%.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium metal (40.2 g, 1.75 mol) was added portion wise to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature and quenched carefully withH₂O (500 mL). The organic layer was separated and concentrated. DCM (500mL) was added to the residue. The solid was filtered off and thefiltrate was concentrated under reduced pressure to afford 20 g oftert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly to next step (yield: 79%).LCMS(A038): m/z 255.3 [M+H]⁺; t_(R)=1.37 min; purity: 99%.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) to afford 17.5g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS(038): m/z 367.2 [M+H]⁺; t_(R)=1.88min; purity: 99%.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol) was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., CH₃I (13.58 g, 95.6 mmol) was added. The mixture was thenstirred at room temperature for 1 h, quenched with H₂O and extractedwith EtOAc (300 mL×3). The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by silica gel column (30% EtOAc/petroleum ether) to afford14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS(039): m/z 381.2 [M+H]⁺; t_(R)=2.17min; purity: 99%.

Step 7: Synthesis of 1-bromo-4-chloro-2-(methoxymethoxy)benzene

Sodium hydride (1.85 g, 46.3 mmol, 60% in mineral oil) was added to astirred solution of 2-bromo-5-chlorophenol (8 g, 38.6 mmol) in 150 mL ofDMF at 0° C. After stirring at 0° C. for 30 min, Methoxy Methyl Bromide(7.25 g, 58 mmol) was added. The mixture was then stirred at roomtemperature for 2 h, quenched with NH₄Cl aqueous solution (15 mL),extracted with EtOAc (30 mL×3). The combined organic layer was driedover anhydrous Na₂SO₄, concentrated and purified by silica gelchromatography (0-10% EtOAc/petroleum ether) which gave 8.1 g of1-bromo-4-chloro-2-(methoxymethoxy)benzene as colorless oil (84% yield).¹H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.3Hz, 1H), 6.89 (dd, J=8.4, 2.3 Hz, 1H), 5.24 (s, 2H). LCMS: t_(R)=1.51min.

Step 8: Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid

A THF solution of n-BuLi (5.76 mL, 14.4 mmol) was added to a stirredsolution of 1-bromo-4-chloro-2-(methoxymethoxy)benzene (3 g, 12 mmol) in40 mL of THF under nitrogen at −78° C. After stirring at −78° C. for 40min, B(OMe)₃ (2 g, 19.2 mmol) was added. The mixture was allowed to warmup to room temperature and stirred for 16 h. NH₄Cl aqueous solution (10mL) was added to the mixture. The mixture was extracted with EtOAc (20mL×3). The combined organic solvents were washed with brine (10 mL),dried over Na₂SO₄, concentrated and recrystallized from 3%EtOAc/petroleum ether to give 1.6 g of4-chloro-2-(methoxymethoxy)phenylboronic acid as off white solid (62%yield). LCMS: m/z 199.1 [M-OH]⁺; t_(R)=1.65 min.

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(6 g, 16.4 mmol), 4-chloro-2-(methoxymethoxy)phenylboronic acid (5.3 g,24.6 mmol), Pd(dppf)Cl₂ (1.6 mg, 2 mmol) and K₂CO₃ (4.53 mg, 32.8 mmol)in 80 mL of dioxane and 8 mL of H₂O was degassed and stirred at 100° C.for 7 h. After cooling to room temperature, the mixture was concentratedand purified by silica gel column (10-60% EtOAc/petroleum ether) whichgave 4.52 g of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (57% yield). LCMS: m/z 517.3 [M+H]⁺; t_(R)=1.86 min.

Step 10: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(14.5 g, 28.1 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.9 g,56.2 mmol), catalyst (2.21 g, 2.82 mmol) and K₃PO₄ (11.9 g, 56.2 mmol)in 100 mL of dioxane and 50 mL of H₂O was degassed and stirred at 100°C. for 5 h. The mixture was concentrated and purified by silica gelcolumn (10-80% EtOAc/petroleum ether) which gave 11.1 g of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (72% yield). LCMS: m/z 549.2 [M+H]⁺; t_(R)=2.09 min.

Step 10: Synthesis of Title Compound:2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A solution of 4N HCl in dioxane (80 ml) was added to a stirred solutionof tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(16 g, 29.2 mmol) in 80 mL of CH₂Cl₂ at room temperature. The mixturewas stirred at room temperature for 3 h and concentrated. The residuewas dissolved in water. pH value was adjusted to 9. The mixture wasextracted with CH₂Cl₂/MeOH (4/1, v/v). The combined organic solventswere concentrated and purified by silica gel chromatography (0-60%MeOH/CH₂Cl₂) to give 11.2 g of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas yellow solid (84% yield).

Example 5: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene

Methoxymethyl bromide (1.25 g, 10 mmol) was added to a stirred solutionof 2-bromo-5-iodophenol (1.5 g, 5 mmol) and K₂CO₃ (1.38 g, 10 mmol) in20 mL of DMF at 0° C. The mixture was then stirred at room temperaturefor 16 h, quenched with 20 mL of H₂O and extracted with EtOAc (20 mL×3).The combined organic solvents were dried over anhydrous Na₂SO₄,concentrated and purified by silica gel column (0-5% EtOAc/petroleumether) to give 1.45 g of 1-bromo-4-iodo-2-(methoxymethoxy)benzene ascolorless liquid (79% yield). LCMS: t_(R)=1.50 min.

Step 2: Synthesis of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (3.3 g, 9.6 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.67 g, 9.6 mmol), Pd(dppf)Cl₂ (866 mg, 1 mmol) and K₂CO₃ (2.66 g, 19.3mmol) in 40 mL of dioxane and 4 mL of H₂O was degassed and stirred at105° C. for 8 h. After cooling to room temperature, the mixture wasextracted with EtOAc (30 mL×3). The combined organic solvents wereconcentrated and purified by silica gel column (10-50% EtOAc/petroleumether) to give 2.5 g of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (69% yield). LCMS: m/z 367.1 [M+H]⁺; t_(R)=2.03 min.

Step 3: Synthesis of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.5 g, 4.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.1 g, 8.2mmol), Pd(dppf)Cl₂ (369 mg, 0.41 mmol) and KOAc (804 mg, 8.2 mmol) in 20mL of dioxane was degassed and stirred at 105° C. for 8 h. The mixturewas filtered, concentrated and purified by silica gel column which gave0.81 g of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (48% yield). LCMS: m/z 415.3 [M+H]⁺; t_(R)=2.10 min.

Step 4: Synthesis of N1,N5-dimethoxy-N1,N5-dimethylglutaramide

Glutaroyl dichloride (50 g, 0.299 mol) was added to a stirred solutionof N,O-dimethylhydroxylamine hydrochloride (64 g, 0.658 mmol) and Et₃N(121.2 g, 1.2 mmol) in 1000 mL of CH₂Cl₂ at 0° C. over 30 min. Thereaction mixture was allowed to room temperature and stirred for 3 h.500 mL of water was added to the mixture, which was extracted withCH₂Cl₂ (1000 mL×3). The combined organic layers were washed with 1% HClsolution, brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford 55 g ofN1,N5-dimethoxy-N1,N5-dimethylglutaramide as brown oil (85% yield),which was used for next step without further purification. LCMS: m/z219.2 [M+H]⁺; t_(R)=1.26 min.

Step 5: Synthesis of heptane-2,6-dione

Methyl magnesium bromide (250 mL, 0.756 mol) was added to a stirredsolution of N1,N5-dimethoxy-N1,N5-dimethylglutaramide (55 g, 0.252 mol)in 800 mL of dry THF at 0° C. over 30 min. After all the Grignardreagent was added, the reaction mixture was allowed to warm to roomtemperature and stirred for 2 h. Water, 50 mL, was added to the mixturefollowed by 1% HCl aqueous solution 300 mL. The mixture was extractedwith ethyl acetate (1000 mL×3). The combined organic layers were washedwith 1% HCl aqueous solution, brine, dried over anhydrous Na₂SO₄,concentrated under reduced pressure and purified by silica gel column(10-50% ethyl acetate in petroleum ether) to afford 13 g ofheptane-2,6-dione as brownish solid (40% yield). LCMS: m/z 129.1 [M+H]⁺;t_(R)=1.24 min.

Step 6: Synthesis of 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one

Ammonium Acetate (18.3 g, 0.238 mol) and acetone dicarboxylic acid (34.7g, 0.238 mol) were added to a stirred solution of heptane-2,6-dione(5.07 g, 39.6 mmol) in AcOH (49 mL) at room temperature. The reactionmixture was then stirred for 3 h at 80° C. The mixture was cooled to 0°C. and diluted with CH₂Cl₂ and water. The aqueous phase was separatedand acidified with 10% HCl aqueous solution (pH=1) and then diluted withEtOAc. The resultant mixture was extracted with water. The combinedaqueous layers were basified with 20% NaOH (pH=11) and extracted withCH₂Cl₂ (three times). The combined organic layers were dried over K₂CO₃and concentrated under reduced pressure. The residue was purified byflash silica gel column chromatography (50% ethyl acetate in petroleumether to 10% MeOH in CH₂Cl₂) to afford1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (2.0 g, 30% yield) as darkred oil. LCMS: m/z 168.2 [M+H]⁺; t_(R)=1.24 min.

Step 7: Synthesis of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one

A solution of 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (2.0 g, 11.98mmol), K₂CO₃ (3.3 g, 24 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.2g, 14.4 mmol.) in 50 mL of acetone was heated to reflux for 16 h undernitrogen protection. The reaction mixture was cooled to roomtemperature, 50 mL of water was added to this mixture which wasextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, concentrated andpurified by silica gel chromatography (10-30% ethyl acetate in petroleumether) which gave9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one asyellowish solid (2.4 g, 70% yield). LCMS: m/z 288.2 [M+H]⁺; t_(R)=1.22min.

Step 8: Synthesis of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime

A solution of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (8.5 g,29.62 mmol) and NH₂OH HCl (4.1 g, 60 mmol) in 150 mL of ethanol washeated to 85° C. for 3 h. Then the mixture was concentrated to residuewhich was dissolved in water and adjusted pH to 8 with aqueous solutionof Na₂CO₃. The mixture was extracted with ethyl acetate (200 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated which gave9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime aswhite solid (8.1 g, 90% yield). LCMS: m/z 303.1 [M+H]⁺; t_(R)=1.19 min.

Step 9: Synthesis of(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine

Sodium (6.72 g, 280 mmol) was added to a stirred solution of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime(8.1 g, 26.82 mmol) in 100 mL of propanol in portions at 105° C. Afterthe addition, the reaction was stirred at 105° C. for 1 h. The reactionmixture was concentrated and 100 mL of water was added. The mixture wasextracted with ethyl acetate (150 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated toafford(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amineas colorless oil (6.3 g, 82% yield). LCMS: m/z 289.1 [M+H]⁺; t_(R)=1.18min.

Step 10: Synthesis of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A solution of(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine(6.3 g, 21.88 mmol), 3,6-dichloropyridazine (3.9 g, 26.26 mmol) andDIPEA (5.4 g, 42 mmol) in 100 mL of DMSO was heated to 140° C. for 6 hunder nitrogen protection. The reaction mixture was cooled to roomtemperature. 100 mL of water was added to this mixture and extractedwith ethyl acetate (105 mL×3). The combined organic layers were washedwith saturated NH₄Cl aqueous solution, brine, dried over anhydrousNa₂SO₄, concentrated and purified by silica gel chromatography (10-50%ethyl acetate in petroleum ether) which gave(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amineas brown solid (4.2 g, 50% yield). LCMS: m/z 401.2 [M+H]⁺; t_(R)=1.39min.

Step 11: Synthesis of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

Sodium hydride (768 mg, 16 mmol, 60% in mineral oil) was added to astirred solution of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine(4.2 g, 10.5 mmol) in 100 mL of THF at room temperature. After thereaction was stirred for 30 min, methyl iodide (1.78 g, 12.6 mmol) wasadded to the mixture. The reaction was heated to 50° C. for 6 h. Thereaction mixture was cooled to room temperature, quenched with 50 mL ofwater and extracted with ethyl acetate (100 mL×3). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, concentratedand purified by silica gel chromatography (10-60% ethyl acetate inpetroleum ether) which gave(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas brown solid (2.7 g, 60% yield). LCMS: m/z 415.2 [M+H]⁺; t_(R)=1.42min.

Step 12: Synthesis of(1R,3s,5S)-9-(4-methoxybenzyl)-N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A mixture of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(120 mg, 0.3 mmol),4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(120 mg, 0.3 mmol), Pd(dppf)Cl₂ (22 mg, 0.03 mmol) and K₂CO₃ (81 mg, 0.6mmol) in 5 mL of dioxane and 1 mL of H₂O was degassed and stirred at 85°C. for 6 h. After cooling to room temperature, the mixture was extractedwith EtOAc (30 mL×3). The combined organic solvents were concentratedand purified by silica gel column (10-50% EtOAc/petroleum ether) whichgave 100 mg g of(1R,3s,5S)-9-(4-methoxybenzyl)-N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas yellowish solid (50% yield). LCMS: m/z 667.5 [M+H]⁺; t_(R)=1.51 min.

Step 13: Synthesis of(1R,3s,5S)—N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A solution of(1R,3s,5S)-9-(4-methoxybenzyl)-N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(100 mg, 0.15 mmol) and Pd(OH)₂ (100 mg) in MeOH (5 mL) was stirred atroom temperature under a balloon of hydrogen for 6 h. The mixture wasfiltered through a pad of celite and concentrated which gave(1R,3s,5S)—N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas yellowish solid (52 mg, 78% in yield). LCMS: m/z 547.3 [M+H]⁺;t_(R)=1.54 min.

Step 13: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A solution of(1R,3s,5S)—N-(6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(52 mg, 0.095 mmol) in 10 mL of HCl in dioxane (4N) was stirred at roomtemperature for 3 h. The reaction mixture was concentrated. A solutionof Ammonia in methanol (7 N) was added to adjust the pH to 9. Themixture was concentrated and purified by silica gel column (80%MeOH/EtOAc) which gave 25 mg of2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas yellow solid (60% yield). ¹H NMR (500 MHz, Methanol-d₄) δ 8.15 (d,J=9.9 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.33(d, J=9.8 Hz, 1H), 7.21-7.20 (m, 2H), 6.08-6.03 (m, 1H), 2.99 (s, 3H),2.45-2.42 (m, 1H), 2.15-1.76 (m, 9H), 1.48 (s, 6H). LCMS: m/z 419.2.0[M+H]⁺; t_(R)=1.34 min.

Example 6: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C. After theaddition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1 g, 515mmol) in 667 mL of H₂O was added. The pH value was adjusted to −9 byusing 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) which gave 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) which gave 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS: m/z 198.1 [M-55]⁺; t_(R)=1.40 min.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and NaOAc (10.8g, 132 mmol) in 250 mL of EtOH was stirred at 70° C. for 4 h. Themixture was concentrated. 200 mL of EtOAc and 60 mL of H₂O was added.The organic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated to give 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS: m/z269.2 [M+H]⁺; t_(R)=1.92 min.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium (40.2 g, 1.75 mol) was added in portions to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature, quenched with H₂O (500 mL).The organic layer was separated and concentrated. DCM (500 mL) was addedto the residue. The solid was filtered off and the filtrate wasconcentrated under reduced pressure to afford 20 g of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly to next step (yield: 79%).LCMS: m/z 255.3 [M+H]⁺; t_(R)=1.37 min.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) to afford 17.5g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS: m/z 367.2 [M+H]⁺; t_(R)=1.88 min.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol, 60% in mineral oil) was added to astirred solution of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., CH₃I (13.58 g, 95.6 mmol) was added. The mixture was thenstirred at room temperature for 1 h, quenched with H₂O and extractedwith EtOAc (300 mL×3). The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by silica gel column (30% EtOAc/petroleum ether) to afford14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS: m/z 381.2 [M+H]⁺; t_(R)=2.17 min.

Step 7: Synthesis of 2-bromo-5-chloro-4-fluorophenol

Bromine (3.52 g, 22 mmol) was added to a stirred solution of3-chloro-4-fluorophenol (4.02 g, 20 mmol) in 80 mL of CH₂C2 at roomtemperature. The mixture was stirred at room temperature for 18 h andquenched with 10 mL of aqueous Na₂S₂O₃ solution. The organic phase wascollected, concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to afford 2.5 g of2-bromo-5-chloro-4-fluorophenol as white solid (44% yield). ¹H NMR (500MHz, Chloroform-d) δ 7.29 (d, J=8.0 Hz, 1H), 7.08 (d, J=6.6 Hz, 1H),5.45 (s, 1H). LCMS: t_(R)=1.44 min.

Step 8: Synthesis of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene

Sodium hydride (215 mg, 5.4 mmol) was added to a stirred solution of2-bromo-5-chloro-4-fluorophenol (1 g, 4.48 mmol) in 14 mL of DMF at 0°C. After stirring for 30 min, bromo(methoxy)methane (428 mg, 8 mmol) wasadded. The mixture was then stirred at room temperature for 2 h,quenched with 10 mL of saturated NH₄Cl aqueous solution and extractedwith EtOAc (30 mL×3). The combined organic solvents were concentratedand purified by silica gel silica gel column (0-8% EtOAc/petroleumether) to give 1.01 g of1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene as white solid (70%yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J=8.1 Hz, 1H), 7.23(d, J=6.6 Hz, 1H), 5.20 (s, 2H), 3.52 (s, 3H).

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (8.5 g,31.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(12.1 g, 47.5 mmol), Pd(dppf)Cl₂(1.86 g, 2.54 mmol) and potassiumacetate (6.2 g, 63.4 mmol) in 200 mL of dioxane was degassed and stirredat 100° C. for 8 h. After cooling to room temperature, tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(8 g, 21.2 mmol), K₂CO₃ (5.8 g, 42.3 mmol) and H₂O (30 mL) were added.The mixture was stirred at 100° C. for 3 h, concentrated and purified bysilica gel column (10-25% EtOAc/petroleum ether) which gave 6-g oftert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas light yellow solid (53% yield). LCMS: m/z 535.2 [M+H]⁺; t_(R)=2.40min.

Step 10: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(120 mg, 0.22 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.34mmol), Pd(dppf)Cl₂ (20 mg, 0.028 mmol) and K₂CO₃ (77 mg, 0.56 mmol) in 2mL of 1,4-dioxane and 0.4 mL of water was purged with nitrogen andsealed. The mixture was stirred at 130° C. under MW for 2 h,concentrated and purified by silica gel chromatography (0-20%MeOH/CH₂Cl₂) which gave 90 mg of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (72% yield). LCMS: m/z 567.2 [M+H]⁺; t_(R)=1.59 min.

Step 11: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol

A solution HCl in dioxane (4 N, 4 ml) was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(90 mg, 0.16 mmol) in 2 mL of CH₂Cl₂. The mixture was stirred at roomtemperature for 2 h, concentrated under reduced pressure, neutralizedwith NH₃/MeOH and purified by prep-HPLC to give 32 mg of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenolas a yellow solid (54% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 13.56 (s,1H), 13.14 (s, 1H), 8.21 (d, J=9.9 Hz, 1H), 8.11 (s, 2H), 7.81 (d,J=12.6 Hz, 1H), 7.35 (d, J=9.9 Hz, 1H), 7.30 (d, J=7.0 Hz, 1H),5.00-4.87 (m, 1H), 2.93 (s, 3H), 1.83-1.77 (m, 2H), 1.56-1.39 (m, 6H),1.17 (s, 6H). LCMS(A038): m/z 423.3[M+H]⁺; t_(R)=1.36 min.

Example 7: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of N1,N5-dimethoxy-N1,N5-dimethylglutaramide

Glutaroyl dichloride (50 g, 0.299 mol) was added to a stirred solutionof N,O-dimethylhydroxylamine hydrochloride (64 g, 0.658 mmol) and Et₃N(121.2 g, 1.2 mmol) in 1000 mL of CH₂Cl₂ at 0° C. over 30 min. Thereaction mixture was allowed to room temperature and stirred for 3 h.500 mL of water was added to the mixture, which was extracted withCH₂Cl₂ (1000 mL×3). The combined organic layers were washed with 1% HClsolution, brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure which gave 55 g ofN1,N5-dimethoxy-N1,N5-dimethylglutaramide as brown oil (85% yield),which was used for next step without further purification. LCMS: m/z219.2 [M+H]⁺; t_(R)=1.26 min.

Step 2: Synthesis of heptane-2,6-dione

Methyl magnesium bromide (250 mL, 0.756 mol) was added to a stirredsolution of N1,N5-dimethoxy-N1,N5-dimethylglutaramide (55 g, 0.252 mol)in 800 mL of THF at 0° C. over 30 min. The reaction mixture was allowedto warm to room temperature and stirred for 2 h. 50 mL of water wasadded to the mixture followed by 1% HCl aqueous solution 300 mL. Themixture was extracted with ethyl acetate (1000 mL×3). The combinedorganic layers were washed with 1% HCl aqueous solution, brine, driedover anhydrous Na₂SO₄, concentrated under reduced pressure and purifiedby silica gel column (10-50% ethyl acetate in petroleum ether) whichgave 13 g of heptane-2,6-dione as brownish solid (40% yield). LCMS: m/z129.1 [M+H]⁺; t_(R)=1.24 min.

Step 3: Synthesis of 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one

Ammonium acetate (18.3 g, 0.238 mol) and acetone dicarboxylic acid (34.7g, 0.238 mol) were added to a stirred solution of heptane-2,6-dione(5.07 g, 39.6 mmol) in AcOH (49 mL) at room temperature. The reactionmixture was then stirred for 3 h at 80° C. The mixture was cooled to 0°C. and diluted with CH₂Cl₂ and water. The aqueous phase was separatedand acidified with 10% HCl aqueous solution (pH=1) and then diluted withAcOEt. The resultant mixture was extracted with water. The combinedaqueous layers were basified with 20% NaOH (pH=11) and extracted withCH₂Cl₂ (three times). The combined organic layers were dried over K₂CO₃and concentrated under reduced pressure. The residue was purified byflash silica gel column chromatography (50% ethyl acetate in petroleumether to 10% MeOH in CH₂Cl₂) which gave1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (2.0 g, 30% yield) as darkred oil. LCMS: m/z 168.2 [M+H]⁺; t_(R)=1.24 min.

Step 4: Synthesis of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one

A solution of 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (2.0 g, 11.98mmol), K₂CO₃ (3.3 g, 24 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.2g, 14.4 mmol.) in 50 mL of acetone was heated to reflux for 16 h undernitrogen protection. The reaction mixture was cooled to roomtemperature, 50 mL of water was added to this mixture which wasextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, concentrated andpurified by silica gel chromatography (10-30% ethyl acetate in petroleumether) which gave9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one asyellowish solid (2.4 g, 70% yield). LCMS: m/z 288.2 [M+H]⁺; t_(R)=1.22min.

Step 5: Synthesis of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime

A solution of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (8.5 g,29.62 mmol) and NH₂OH HCl (4.1 g, 60 mmol) in 150 mL of ethanol washeated to 85° C. for 3 h. Then the mixture was concentrated to residuewhich was dissolved in water and adjusted pH to 8 with aqueous solutionof Na₂CO₃. Tithe mixture was extracted with ethyl acetate (200 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated which gave9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime aswhite solid (8.1 g, 90% yield). LCMS: m/z 303.1 [M+H]⁺; t_(R)=1.19 min.

Step 6: Synthesis of(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine

Sodium (6.72 g, 280 mmol) was added to a stirred solution of9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one oxime(8.1 g, 26.82 mmol) in 100 mL of propanol in portions at 105° C. Afterthe addition, the reaction was stirred at 105° C. for 1 h. The reactionmixture was concentrated and 100 mL of water was added. The mixture wasextracted with ethyl acetate (150 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedwhich gave(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amineas colorless oil (6.3 g, 82% yield). LCMS: m/z 289.1 [M+H]⁺; t_(R)=1.18min.

Step 7: Synthesis of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A solution of(1R,3s,5S)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine(6.3 g, 21.88 mmol), 3,6-dichloropyridazine (3.9 g, 26.26 mmol) andDIPEA (5.4 g, 42 mmol) in 100 mL of DMSO was heated to 140° C. for 6 hunder nitrogen protection. The reaction mixture was cooled to roomtemperature. 100 mL of water was added to this mixture and extractedwith ethyl acetate (105 mL×3). The combined organic layers were washedwith saturated NH₄Cl aqueous solution, brine, dried over anhydrousNa₂SO₄, concentrated and purified by silica gel chromatography (10-50%ethyl acetate in petroleum ether) which gave(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amineas brown solid (4.2 g, 50% yield). LCMS: m/z 401.2 [M+H]⁺; t_(R)=1.39min.

Step 8: Synthesis of(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

Sodium hydride (768 mg, 16 mmol, 60% in mineral oil) was added to astirred solution of(1S,3R)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-amine(4.2 g, 10.5 mmol) in 100 mL of THF at room temperature. After thereaction was stirred for 30 min, methyl iodide (1.78 g, 12.6 mmol) wasadded to the mixture. The reaction was heated to 50° C. for 6 h. Thereaction mixture was cooled to room temperature, quenched with 50 mL ofwater and extracted with ethyl acetate (100 mL×3). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, concentratedand purified by silica gel chromatography (10-60% ethyl acetate inpetroleum ether) which gave(1S,3R)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas brown solid (2.7 g, 60% yield). LCMS: m/z 415.2 [M+H]⁺; t_(R)=1.42min.

Step 9: Synthesis of 2-bromo-5-chloro-4-fluorophenol

Bromine (3.52 g, 22 mmol) was added to a stirred solution of3-chloro-4-fluorophenol (4.02 g, 20 mmol) in 80 mL of CH₂Cl₂ at roomtemperature. The mixture was stirred at room temperature for 18 h andquenched with 10 mL of aqueous Na₂S2O₃ solution. The organic phase wascollected, concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) which gave 2.5 g of2-bromo-5-chloro-4-fluorophenol as white solid (44% yield). ¹H NMR (500MHz, Chloroform-d) δ 7.29 (d, J=8.0 Hz, 1H), 7.08 (d, J=6.6 Hz, 1H),5.45 (s, 1H). LCMS: t_(R)=1.44 min.

Step 10: Synthesis of1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene

Sodium hydride (215 mg, 5.4 mmol, 60% in mineral oil) was added to astirred solution of 2-bromo-5-chloro-4-fluorophenol (1 g, 4.48 mmol) in14 mL of DMF at 0° C. After stirring for 30 min, bromo(methoxy)methane(428 mg, 8 mmol) was added. The mixture was then stirred at roomtemperature for 2 h, quenched with 10 mL of saturated NH₄Cl aqueoussolution and extracted with EtOAc (30 mL×3). The combined organicsolvents were concentrated and purified by silica gel silica gel column(0-8% EtOAc/petroleum ether) which gave 1.01 g of1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene as white solid (70%yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J=8.1 Hz, 1H), 7.23(d, J=6.6 Hz, 1H), 5.20 (s, 2H), 3.52 (s, 3H).

Step 11: Synthesis of(1R,3s,5S)—N-(6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A mixture of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (600mg, 2.22 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (677 mg,2.66 mmol), Pd(dppf)Cl₂ (325 mg, 0.44 mmol) and KOAc (435 mg, 4.44 mmol)in 8 mL of dioxane was degassed and stirred at 100° C. for 6 h. Themixture was cooled to room temperature,(1R,3s,5S)—N-(6-chloropyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(735 mg, 1.78 mmol), Pd(dppf)Cl₂ (325 mg, 0.44 mmol), K₂CO₃ (613 mg,4.44 mmol) and 1 mL of H₂O was added. The mixture was degassed andstirred at 100° C. for 2 h, concentrated and purified by silica gelcolumn (40% EtOAc/petroleum ether) which gave 615 mg of(1R,3s,5S)—N-(6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas brown solid (49% yield). LCMS: m/z 569.0 [M+H]⁺; t_(R)=2.54 min.

Step 12: Synthesis of(1R,3s,5S)—N-(6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine

A mixture of(1R,3s,5S)—N-(6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(188 mg, 0.33 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65 mg, 0.33mmol), catalyst (52 mg, 0.07 mmol) and K₃PO₄ (141 mg, 0.66 mmol) in 2 mLof dioxane and 0.3 mL of H₂O was degassed and stirred at 100° C. for 16h. The mixture was filtered, concentrated and purified by silica gelcolumn (40-100% EtOAc/petroleum ether) which gave 113 mg of(1R,3s,5S)—N-(6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amineas white solid (57% yield). LCMS: m z 601.2 [M+H]⁺; t_(R)=2.27 min.

Step 13: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol

A mixture of(1R,3s,5S)—N-(6-(5-fluoro-2-(methoxymethoxy)-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)-9-(4-methoxybenzyl)-N,1,5-trimethyl-9-azabicyclo[3.3.1]nonan-3-amine(113 mg, 0.19 mmol) in 10 mL of TFA was stirred at 70° C. for 72 h. Thereaction mixture was concentrated, NH₃/MeOH (7 N) was added to makepH=9, concentrated and purified by silica gel column (80% MeOH/EtOAc)which gave2-(6-(((1R,3s,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoro-5-(1H-pyrazol-4-yl)phenol(13 mg, 16% yield). H NMR (500 MHz, DMSO-d₆) δ 13.52 (s, 1H), 13.13 (s,1H), 8.22 (d, J=10.1 Hz, 1H), 8.18-7.91 (m, 2H), 7.80 (d, J=12.7 Hz,1H), 7.29 (dd, J=11.7, 8.3 Hz, 2H), 5.74 (m, 1H), 2.88 (s, 2H),2.15-1.99 (m, 1H), 1.63 (m, 5H), 1.56-1.24 (m, 4H), 1.05 (s, 6H). LCMS:m/z 437.0 [M+H]⁺; t_(R)=1.77 min.

Example 8: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydride (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C. After theaddition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1 g, 515mmol) in 667 mL of H₂O was added. The pH value was adjusted to ˜9 byusing 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) which gave 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min; purity: 85%.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) which gave 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS: m/z 198.1 [M-55]⁺; t_(R)=1.40 min; purity:100%.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and NaOAc (10.8g, 132 mmol) in 250 mL of EtOH was stirred at 70° C. for 4 h. Themixture was concentrated. 200 mL of EtOAc and 60 mL of H₂O was added.The organic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated to give 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS: m/z269.2 [M+H]⁺; t_(R)=1.92 min; purity: 100%.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium (40.2 g, 1.75 mol) was added in portions to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature, quenched with H₂O (500 mL).The organic layer was separated and concentrated. DCM (500 mL) was addedto the residue. The solid was filtered off and the filtrate wasconcentrated under reduced pressure which gave 20 g of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly to next step (yield: 79%).LCMS: m/z 255.3 [M+H]⁺; t_(R)=1.37 min; purity: 99%.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) which gave17.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS: m/z 367.2 [M+H]⁺; t_(R)=1.88 min;purity: 99%.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol) was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., iodomethane (13.58 g, 95.6 mmol) was added. The mixture wasthen stirred at room temperature for 1 h, quenched with H₂O andextracted with EtOAc (300 mL×3). The combined organic phases were washedwith brine, dried over anhydrous Na₂SO₄, concentrated under reducedpressure and purified by silica gel column (30% EtOAc/petroleum ether)which gave 14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS: m/z 381.2 [M+H]⁺; t_(R)=2.17 min;purity: 99%.

Step 7: Synthesis of 1-bromo-4-chloro-2-(methoxymethoxy)benzene

Sodium hydride (185 g, 46.3 mmol, 60% in mineral oil) was added to astirred solution of 2-bromo-5-chlorophenol (8 g, 38.6 mmol) in 150 mL ofDMF at 0° C. After stirring at 0° C. for 30 min, MOMBr (7.25 g, 58 mmol)was added. The mixture was then stirred at room temperature for 2 h,quenched with NH₄Cl aqueous solution (15 mL), extracted with EtOAc (30mL×3). The combined organic solvents were dried over anhydrous Na₂SO₄,concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) which gave 8.1 g of1-bromo-4-chloro-2-(methoxymethoxy)benzene as colorless oil (84% yield).¹H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.3Hz, 1H), 6.89 (dd, J=8.4, 2.3 Hz, 1H), 5.24 (s, 2H). LCMS: t_(R)=1.51min.

Step 8: Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid

A solution of n-BuLi in hexane (5.76 mL, 14.4 mmol) was added to astirred solution of 1-bromo-4-chloro-2-(methoxymethoxy)benzene (3 g, 12mmol) in 40 mL of THF under nitrogen at −78° C. After stirring at −78°C. for 40 min, B(OMe)₃ (2 g, 19.2 mmol) was added. The mixture wasallowed to warm up to room temperature and stirred for 16 h. NH₄Claqueous solution (10 mL) was added to the mixture. The mixture wasextracted with EtOAc (20 mL×3). The combined organic solvents werewashed with brine (10 mL), dried over Na₂SO₄, concentrated andrecrystallized from 3% EtOAc/petroleum ether which gave 1.6 g of4-chloro-2-(methoxymethoxy)phenylboronic acid as off white solid (62%yield). LCMS: m/z 199.1 [M-OH]⁺; t_(R)=1.65 min.

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(6 g, 16.4 mmol), 4-chloro-2-(methoxymethoxy)phenylboronic acid (5.3 g,24.6 mmol), Pd(dppf)Cl₂ (1.6 mg, 2 mmol) and K₂CO₃ (4.53 mg, 32.8 mmol)in 80 mL of dioxane and 8 mL of H₂O was degassed and stirred at 100° C.for 7 h. After cooling to room temperature, the mixture was concentratedand purified by silica gel column (10-60% EtOAc/petroleum ether) whichgave 4.52 g of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (57% yield). LCMS: m/z 517.3 [M+H]⁺; t_(R)=1.86 min.

Step 10: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(4 g, 7.75 mmol), 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid(1.77 g, 11.6 mmol), catalyst (610 mg mg, 0.78 mmol) and K₃PO₄ (3.29 g,15.5 mmol) in 30 mL of dioxane and 10 mL of H₂O was degassed and stirredat 100° C. for 6 h. The mixture was filtered, concentrated and purifiedby silica gel column (0-15% MeOH/EtOAc) which gave 4.2 g of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (77% yield). LCMS: m/z 590.2 [M+H]⁺; t_(R)=2.09 min.

Step 11: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one

A solution of 30 mL of 4N HCl in dioxane was added to a stirred solutionof (1R,3s,5S)-tert-butyl3-((6-(2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(3 g, 5.1 mmol) in 20 mL of CH₂C2 and 20 mL of MeOH. The mixture wasstirred at room temperature for 3 h, concentrated under reducedpressure. The residue was dissolved in water. K₂CO₃ aqueous solution wasadded to adjust pH=9. The solid was collected and dried in vacuo whichgave 2.15 g of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one as yellowsolid (80% yield).

¹H NMR (500 MHz, DMSO-d₆) δ 13.75 (s, 1H), 8.25 (d, J=10.0 Hz, 1H), 7.97(d, J=8.2 Hz, 1H), 7.78 (d, J=7.1 Hz, 1H), 7.38 (d, J=9.9 Hz, 1H),7.29-7.22 (m, 2H), 6.70 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 4.94 (s, 1H),3.46 (s, 3H), 2.94 (s, 3H), 1.88-1.83 (m, 2H), 1.61-1.42 (m, 6H), 1.23(s, 6H). LCMS: m/z 446.1 [M+H]⁺; t_(R)=1.72 min.

Example 9: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(11H)-one

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C.

After the addition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1g, 515 mmol) in 667 mL of H₂O was added. The pH value was adjusted to ˜9by using 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) to give 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) to give 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS: m/z 198.1 [M-55]⁺; t_(R)=1.40 min.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and NaOAc (10.8g, 132 mmol) in 250 mL of EtOH was stirred at 70° C. for 4 h. Themixture was concentrated. 200 mL of EtOAc and 60 mL of H₂O was added.The organic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated to give 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS: m/z269.2 [M+H]⁺; t_(R)=1.92 min.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium (40.2 g, 1.75 mol) was added in portions to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature, quenched with H₂O (500 mL).The organic layer was separated and concentrated. DCM (500 mL) was addedto the residue. The solid was filtered off and the filtrate wasconcentrated under reduced pressure to afford 20 g of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly to next step (yield: 79%).LCMS: m/z 255.3 [M+H]⁺; t_(R)=1.37 min.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) to afford 17.5g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS: m/z 367.2 [M+H]⁺; t_(R)=1.88 min.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol, 60% in mineral oil) was added to astirred solution of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., CH₃I (13.58 g, 95.6 mmol) was added. The mixture was thenstirred at room temperature for 1 h, quenched with H₂O and extractedwith EtOAc (300 mL×3). The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by silica gel column (30% EtOAc/petroleum ether) to afford14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS: m/z 381.2 [M+H]⁺; t_(R)=2.17 min.

Step 7: Synthesis of 2-bromo-5-chloro-4-fluorophenol

Bromine (3.52 g, 22 mmol) was added to a stirred solution of3-chloro-4-fluorophenol (4.02 g, 20 mmol) in 80 mL of CH₂C₂ at roomtemperature. The mixture was stirred at room temperature for 18 h andquenched with 10 mL of aqueous Na₂S2O₃ solution. The organic phase wascollected, concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to afford 2.5 g of2-bromo-5-chloro-4-fluorophenol as white solid (44% yield). ¹H NMR (500MHz, Chloroform-d) δ 7.29 (d, J=8.0 Hz, 1H), 7.08 (d, J=6.6 Hz, 1H),5.45 (s, 1H). LCMS: t_(R)=1.44 min.

Step 8: Synthesis of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene

Sodium hydride (215 mg, 5.4 mmol) was added to a stirred solution of2-bromo-5-chloro-4-fluorophenol (1 g, 4.48 mmol) in 14 mL of DMF at 0°C. After stirring for 30 min, bromo(methoxy)methane (428 mg, 8 mmol) wasadded. The mixture was then stirred at room temperature for 2 h,quenched with 10 mL of saturated NH₄Cl aqueous solution and extractedwith EtOAc (30 mL×3). The combined organic solvents were concentratedand purified by silica gel silica gel column (0-8% EtOAc/petroleumether) to give 1.01 g of1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene as white solid (70%yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J=8.1 Hz, 1H), 7.23(d, J=6.6 Hz, 1H), 5.20 (s, 2H), 3.52 (s, 3H).

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (8.5 g,31.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(12.1 g, 47.5 mmol), Pd(dppf)Cl₂(1.86 g, 2.54 mmol) and KOAc (6.2 g,63.4 mmol) in 200 mL of dioxane was degassed and stirred at 100° C. for8 h. After cooling to room temperature, tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(8 g, 21.2 mmol), K₂CO₃ (5.8 g, 42.3 mmol) and H₂O (30 mL) were added.The mixture was stirred at 100° C. for 3 h, concentrated and purified bysilica gel column (10-25% EtOAc/petroleum ether) which gave 6 g oftert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas light yellow solid (53% yield). LCMS: m/z 535.2 [M+H]⁺; t_(R)=2.40min.

Step 10: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(120 mg, 0.22 mmol), 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid(63 mg, 0.27 mmol), Pd(dppf)Cl₂ (20 mg, 0.028 mmol) and K₂CO₃ (77 mg,0.56 mmol) in 2 mL of 1,4-dioxane and 0.4 mL of water was purged withnitrogen and sealed. The mixture was stirred at 130° C. under MW for 2h, concentrated and purified by silica gel chromatography (0-10%MeOH/CH₂Cl₂) which gave 110 mg of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (82% yield). LCMS: m/z 608.2 [M+H]⁺; t_(R)=1.59 min.

Step 11: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one

To a stirred solution of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-2-(methoxymethoxy)-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(100 mg, 0.16 mmol) in 2 mL of CH₂Cl₂ was added 4 mL of a 4N solution ofHCl in dioxane. The mixture was stirred at room temperature for 2 h,concentrated under reduced pressure, neutralized with NH₃/MeOH andpurified by prep-HPLC to give 37 mg of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-methylpyridin-2(1H)-oneas a yellow solid (50% yield).

Example 10: Synthesis of2-(6-((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C.

After the addition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1g, 515 mmol) in 667 mL of H₂O was added. The pH value was adjusted to ˜9by using 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) which gave 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min.

Step 2: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ol

Sodium borohydride (224 mg, 5.88 mmol) was added to a stirred solutionof 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (600 mg, 3.92 mmol) in 10mL of methanol at 0° C. The mixture was stirred at room temperature for3 h and concentrated. 100 mL of EtOAc and 60 mL of H₂O was added. Theorganic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated which gave 600 mg of a mixture ofisomers of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ol as white solid(yield: 99%). LCMS: m z 156.3 [M+H]⁺; t_(R)=0.28 min.

Step 3: Synthesisof(1R,3s,5S)-3-(6-chloropyridazin-3-yloxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane

Sodium hydride (129 mg, 3.23 mmol, 60% in mineral oil) was added to amixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ol (200 mg, 1.29mmol) in THF (10 mL) at room temperature. The mixture was stirred atroom temperature for 30 minutes. Then 3,6-dichloropyridazine (210 mg,1.42 mmol) was added. The mixture was stirred at 50° C. for 18 hours.After cooling to room temperature, the mixture was quenched with 20 mLof water, extracted with EtOAc (20 mL×3). The combined organic solventswere washed with water (10 mL), concentrated and isomers were purifiedby silica gel column (0-10% MeOH/DCM) which gave 45 mg of(1R,3s,5S)-3-(6-chloropyridazin-3-yloxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octaneas white solid (13% yield). LCMS: m/z 268.1 [M+H]⁺; t_(R)=1.56 min.

Step 4: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene

Methoxymethyl bromide (1.25 g, 10 mmol) was added to a stirred solutionof 2-bromo-5-iodophenol (1.5 g, 5 mmol) and K₂CO₃ (1.38 g, 10 mmol) in20 mL of DMF at 0° C. The mixture was then stirred at room temperaturefor 16 h, quenched with 20 mL of H₂O and extracted with EtOAc (20 mL×3).The combined organic solvents were dried over anhydrous Na₂SO₄,concentrated and purified by silica gel column (0-5% EtOAc/petroleumether) to give 1.45 g of 1-bromo-4-iodo-2-(methoxymethoxy)benzene ascolorless liquid (79% yield). LCMS: t_(R)=1.50 min.

Step 5: Synthesis of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (3.3 g, 9.6 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.67 g, 9.6 mmol), Pd(dppf)Cl₂ (866 mg, 1 mmol) and K₂CO₃ (2.66 g, 19.3mmol) in 40 mL of dioxane and 4 mL of H₂O was degassed and stirred at105° C. for 8 h. After cooling to room temperature, the mixture wasextracted with EtOAc (30 mL×3). The combined organic solvents wereconcentrated and purified by silica gel column (10-50% EtOAc/petroleumether) which gave 2.5 g of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (69% yield). LCMS: m/z 367.1 [M+H]⁺; t_(R)=2.03 min.

Step 6: Synthesis of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.5 g, 4.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.1 g, 8.2mmol), Pd(dppf)Cl₂ (369 mg, 0.41 mmol) and KOAc (804 mg, 8.2 mmol) in 20mL of dioxane was degassed and stirred at 105° C. for 8 h. The mixturewas filtered, concentrated and purified by silica gel column to give0.81 g of4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleas colorless oil (48% yield). LCMS: m/z 415.3 [M+H]⁺; t_(R)=2.10 min.

Step 7: Synthesis of(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane

A mixture of(1R,3s,5S)-3-(6-chloropyridazin-3-yloxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane(40 mg, 0.15 mmol),4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(81 mg, 0.20 mmol), Pd(dppf)Cl₂ (15 mg, 0.021 mmol) and K₂CO₃ (42 mg,0.30 mmol) in 1.5 mL of 1,4-dioxane and 0.5 mL of water was degassed andstirred at 105° C. for 2 h under nitrogen atmosphere. The mixture wasthen concentrated and purified by silica gel chromatography (1-15%MeOH/DCM) which gave 60 mg of(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octaneas white solid (78% yield). LCMS: m/z 520.3 [M+H]⁺; t_(R)=1.89 min.

Step 8: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

A 1 mL solution of 4 N HCl in dioxane was added to a solution of(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane(60 mg, 0.12 mmol) in 1 mL of CH₂Cl₂ at room temperature. After stirringat room temperature for 1 h, the mixture was concentrated, neutralizedwith ammonium hydroxide and purified by prep-HPLC (NH₄HCO₃) which gave30 mg of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas yellow solid (67% yield).

Example 11: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C. After theaddition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1 g, 515mmol) in 667 mL of H₂O was added. The pH value was adjusted to ˜9 byusing 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) which gave 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min; purity: 85%.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) which gave 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS: m/z 198.1 [M-55]⁺; t_(R)=1.40 min; purity:100%.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and NaOAc (10.8g, 132 mmol) in 250 mL of EtOH was stirred at 70° C. for 4 h. Themixture was concentrated. 200 mL of EtOAc and 60 mL of H₂O was added.The organic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated which gave 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS: m/z269.2 [M+H]⁺; t_(R)=1.92 min; purity: 100%.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium (40.2 g, 1.75 mol) was in portions added to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature, quenched with H₂O (500 mL).The organic layer was separated and concentrated. DCM (500 mL) was addedto the residue. The solid was triturated filtered off and the filtratewas concentrated under reduced pressure to afford 20 g of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly in next step (yield: 79%).LCMS: m/z 255.3 [M+H]⁺; t_(R)=1.37 min; purity: 99%.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) which gave17.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS: m/z 367.2 [M+H]⁺; t_(R)=1.88 min;purity: 99%.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol) was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., CH₃I (13.58 g, 95.6 mmol) was added. The mixture was thenstirred at room temperature for 1 h, quenched with H₂O and extractedwith EtOAc (300 mL×3). The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by silica gel column (30% EtOAc/petroleum ether) which gave14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS: m/z 381.2 [M+H]⁺; t_(R)=2.17 min;purity: 99%.

Step 7: Synthesis of 1-bromo-4-chloro-2-(methoxymethoxy)benzene

Sodium hydride (185 g, 46.3 mmol, 60% in mineral oil) was added to astirred solution of 2-bromo-5-chlorophenol (8 g, 38.6 mmol) in 150 mL ofDMF at 0° C. After stirring at 0° C. for 30 min, MOMBr (7.25 g, 58 mmol)was added. The mixture was then stirred at room temperature for 2 h,quenched with NH₄Cl aqueous solution (15 mL), extracted with EtOAc (30mL×3). The combined organic solvents were dried over anhydrous Na₂SO₄,concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) which gave 8.1 g of1-bromo-4-chloro-2-(methoxymethoxy)benzene as colorless oil (84% yield).¹H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.3Hz, 1H), 6.89 (dd, J=8.4, 2.3 Hz, 1H), 5.24 (s, 2H). LCMS: t_(R)=1.51min.

Step 8: Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid

To a stirred solution of 1-bromo-4-chloro-2-(methoxymethoxy)benzene (3g, 12 mmol) in 40 mL of THF under nitrogen at −78° C. was added n-BuLi(5.76 mL, 14.4 mmol). After stirring at −78° C. for 40 min, B(OMe)₃ (2g, 19.2 mmol) was added. The mixture was allowed to warm up to roomtemperature and stirred for 16 h. NH₄Cl aqueous solution (10 mL) wasadded to the mixture. The mixture was extracted with EtOAc (20 mL×3).The combined organic solvents were washed with brine (10 mL), dried overNa₂SO₄, concentrated and recrystallized from 3% EtOAc/petroleum etherwhich gave 1.6 g of 4-chloro-2-(methoxymethoxy)phenylboronic acid as offwhite solid (62% yield). LCMS: m/z 199.1 [M-OH]⁺; t_(R)=1.65 min.

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(6 g, 16.4 mmol), 4-chloro-2-(methoxymethoxy)phenylboronic acid (5.3 g,24.6 mmol), Pd(dppf)Cl₂ (1.6 mg, 2 mmol) and K₂CO₃ (4.53 mg, 32.8 mmol)in 80 mL of dioxane and 8 mL of H₂O was degassed and stirred at 100° C.for 7 h. After cooling to room temperature, the mixture was concentratedand purified by silica gel column (10-60% EtOAc/petroleum ether) whichgave 4.52 g of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas white solid (57% yield). LCMS: m/z 517.3 [M+H]⁺; t_(R)=1.86 min.

Step 10: Synthesis of 5-chloro-3-methoxypyridazine

Sodium methoxide (5.84 g, 0.108 mol) was added to a stirred solution of3,5-dichloropyridazine (8 g, 0.054 mol) in 350 mL of THF at 0° C. Afterthe addition, the mixture was stirred at room temperature for 16 h. Themixture was quenched with water (100 mL), extracted with EA (300 mL×2).The combined organic solvents were dried over anhydrous Na₂SO₄,concentrated and purified by silica gel chromatography (0-40%EtOAc/petroleum ether) which gave 1.5 g of 5-chloro-3-methoxypyridazineas yellow solid (17% yield). LCMS: m/z 145.1 [M+H]⁺; t_(R)=1.42 min.

Step 11: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(6-methoxypyridazin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(200 mg, 0.39 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (197 mg,0.77 mmol), Pd₂(dba)₃ (32 mg, 0.04 mmol), X-Phos (20 mg, 0.04 mmol) andKOAc (115 mg, 1.2 mmol) in 4 mL of 1,4-dioxane was degassed and stirredat 90° C. for 2 h. After cooling to room temperature, Pd(dppf)Cl₂ (61mg, 0.08), 5-chloro-3-methoxypyridazine (113 mg, 0.78 mmol), K₂CO₃ (163mg, 1.2 mmol) and H₂O (0.3 mL) were added. The mixture was stirred at110° C. for 2 h, concentrated and purified by silica gel column (10-80%EtOAc/petroleum ether) to give 230 mg of tert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(6-methoxypyridazin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas light yellow solid (78% yield). LCMS: m/z 591.2 [M+H]⁺; t_(R)=2.20min.

Step 12: Synthesis of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol

A solution 4 N HCl in dioxane 4 mL was added to a stirred solution oftert-butyl(1R,3s,5S)-3-((6-(2-(methoxymethoxy)-4-(6-methoxypyridazin-4-yl)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(180 mg, 0.3 mmol) in 4 mL of CH₂C2. The mixture was stirred at roomtemperature for 3 h, concentrated under reduced pressure, neutralizedwith NH₃/MeOH and purified by prep-HPLC which gave 58 mg of2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenolas a yellow solid (43% yield).

Example 12: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one

Step 1: Synthesis of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one

Potassium hydroxide (108 g, 1.93 mol) in 70 mL of H₂O was added to astirred solution of 3-oxopentanedioic acid (120 g, 822 mmol) andhexane-2,5-dione (49.2 g, 432 mmol) in 350 mL of H₂O and 0° C. After theaddition, NH₄Cl (70.1 g, 1.32 mol) and NaOAc trihydrate (70.1 g, 515mmol) in 667 mL of H₂O was added. The pH value was adjusted to ˜9 byusing 1 N NaOH aqueous solution. The mixture was stirred at roomtemperature for 72 h during which time the pH value was adjusted to ˜9by using additional 1 N NaOH aqueous solution. The mixture was extractedwith CH₂Cl₂ (1 L×5). The combined organic solvents were dried overanhydrous Na₂SO₄, concentrated and purified by silica gel chromatography(0-25% MeOH/CH₂Cl₂) which gave 16.7 g of1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one as black oil (25% yield).LCMS: m/z 154.2 [M+H]⁺; t_(R)=1.20 min.

Step 2: Synthesis of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (24 g, 163mmol), di-tert-butyl dicarbonate (35.6 g, 326 mmol) and DIPEA (31.5 g,244 mmol) in 500 mL of 1,4-dioxane was stirred at 70° C. for 6 h. Themixture was concentrated and purified by silica gel chromatography(0-30% EtOAc/petroleum ether) which gave 16.7 of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate as whitesolid (yield: 42%). LCMS: m/z 198.1 [M-55]⁺; t_(R)=1.40 min.

Step 3: Synthesis of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (16.7 g, 66mmol), hydroxylamine hydrochloride (18.2 g, 26.4 mmol) and NaOAc (10.8g, 132 mmol) in 250 mL of EtOH was stirred at 70° C. for 4 h. Themixture was concentrated. 200 mL of EtOAc and 60 mL of H₂O was added.The organic phase was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄, concentrated to give 16.7 g of tert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate asyellow solid which was used directly to next step (93% yield). LCMS: m/z269.2 [M+H]⁺; t_(R)=1.92 min.

Step 4: Synthesis of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium (40.2 g, 1.75 mol) was added in portions to a mixture oftert-butyl3-(hydroxyimino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(26.8 g, 0.1 mol) in 1000 mL of n-PrOH was heated to 110° C. over 1 h.After addition, the mixture was stirred at reflux for additional 1 h.The mixture was cooled to room temperature, quenched with H₂O (500 mL).The organic layer was separated and concentrated. DCM (500 mL) was addedto the residue. The solid was filtered off and the filtrate wasconcentrated under reduced pressure which gave 20 g of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow oil, which was used directly to next step (yield: 79%).LCMS: m/z 255.3 [M+H]⁺; t_(R)=1.37 min.

Step 5: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl(1R,3s,5S)-3-amino-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 78.7 mmol), 3,6-dichloropyridazine (23.3 g, 157.5 mmol) and DIPEA(20.48 g, 157.5 mmol) in 500 mL of DMSO was stirred at 120° C. for 24 h.The mixture was cooled to room temperature, quenched with H₂O andextracted with ethyl acetate (500 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. After removal of solvent, the crude product waspurified by silica gel column (50% EtOAc/petroleum ether) which gave17.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (yield: 61%). LCMS: m/z 367.2 [M+H]⁺; t_(R)=1.88 min.

Step 6: Synthesis of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Sodium hydride (2.87 g, 71.7 mmol, 60% in mineral oil) was added to astirred solution of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5 g, 47.8 mmol) in 400 mL of DMF at 0° C. After stirring for 20 minat 0° C., CH₃I (13.58 g, 95.6 mmol) was added. The mixture was thenstirred at room temperature for 1 h, quenched with H₂O and extractedwith EtOAc (300 mL×3). The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by silica gel column (30% EtOAc/petroleum ether) which gave14.5 g of tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas yellow solid (80% yield). LCMS: m/z 381.2 [M+H]⁺; t_(R)=2.17 min.

Step 7: Synthesis of 2-bromo-5-chloro-4-fluorophenol

Bromine (3.52 g, 22 mmol) was added to a stirred solution of3-chloro-4-fluorophenol (4.02 g, 20 mmol) in 80 mL of CH₂Cl₂ at roomtemperature. The mixture was stirred at room temperature for 18 h andquenched with 10 mL of aqueous Na₂S2O₃ solution. The organic phase wascollected, concentrated and purified by silica gel chromatography (0-10%EtOAc/petroleum ether) which gave 2.5 g of2-bromo-5-chloro-4-fluorophenol as white solid (44% yield). ¹H NMR (500MHz, Chloroform-d) δ 7.29 (d, J=8.0 Hz, 1H), 7.08 (d, J=6.6 Hz, 1H),5.45 (s, 1H). LCMS: t_(R)=1.44 min.

Step 8: Synthesis of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene

Sodium hydride (215 mg, 5.4 mmol, 60% in mineral oil) was added to astirred solution of 2-bromo-5-chloro-4-fluorophenol (1 g, 4.48 mmol) in14 mL of DMF at 0° C. After stirring for 30 min, bromo(methoxy)methane(428 mg, 8 mmol) was added. The mixture was then stirred at roomtemperature for 2 h, quenched with 10 mL of saturated NH₄Cl aqueoussolution and extracted with EtOAc (30 mL×3). The combined organicsolvents were concentrated and purified by silica gel silica gel column(0-8% EtOAc/petroleum ether) which gave 1.01 g of1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene as white solid (70%yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J=8.1 Hz, 1H), 7.23(d, J=6.6 Hz, 1H), 5.20 (s, 2H), 3.52 (s, 3H).

Step 9: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (8.5 g,31.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(12.1 g, 47.5 mmol), Pd(dppf)Cl₂(1.86 g, 2.54 mmol) and KOAc (6.2 g,63.4 mmol) in 200 mL of dioxane was degassed and stirred at 100° C. for8 h. After cooling to room temperature, tert-butyl(1R,3s,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(8 g, 21.2 mmol), K₂CO₃ (5.8 g, 42.3 mmol) and H₂O (30 mL) were added.The mixture was stirred at 100° C. for 3 h, concentrated and purified bysilica gel column (10-25% EtOAc/petroleum ether) which gave 6 g oftert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas light yellow solid (53% yield). LCMS: m/z 535.2 [M+H]⁺; t_(R)=2.40min.

Step 10: Synthesis of 4-bromo-1-(fluoromethyl)pyridin-2(1H)-one

Sodium hydride (111 mg, 4.62 mmol, 60% in mineral oil) was added to astirred solution of 4-bromopyridin-2(1H)-one (400 mg, 2.31 mmol) in 15mL of THF at 0° C. After stirring for 20 min at 0° C.,bromofluoromethane (517 mg, 4.62 mmol) was added. The mixture was thenstirred at 50° C. for 1 h, quenched with H₂O and extracted with EtOAc(30 mL×3). The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄, concentrated under reduced pressure and purifiedby silica gel column (50% EtOAc/petroleum ether) which gave 400 mg of4-bromo-1-(fluoromethyl)pyridin-2(1H)-one as white solid (84% yield).LCMS: m/z 207.9 [M+H]⁺; t_(R)=1.46 min.

Step 11: Synthesis of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-4-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of 4-bromo-1-(fluoromethyl)pyridin-2(1H)-one (65 mg, 0.32mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (97mg, 0.38 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol)and KOAc (63 mg, 0.64 mmol) in 4 mL of 1,4-dioxane was degassed andstirred at 90° C. for 8 h. After cooling to room temperature, tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(100 mg, 0.19 mmol), K₂CO₃ (52 mg, 0.38 mmol) and H₂O (0.8 mL) wereadded. The mixture was stirred at 110° C. for 3 h, concentrated andpurified by silica gel column (10-80% EtOAc/petroleum ether) which gave90 mg of tert-butyl(1R,3s,5S)-3-((6-(5-fluoro-4-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylateas light yellow oil (77% yield). LCMS: m/z 626.1 [M+H]⁺; t_(R)=2.19 min.

Step 12: Synthesis of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one

A solution of 4N HCl in dioxane (4 mL) was added to a stirred solutionof tert-butyl(1R,3s,5S)-3-((6-(4-chloro-5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-3-yl)(methyl)amino)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate(90 mg, 0.14 mmol) in 4 mL of CH₂CO₂. The mixture was stirred at roomtemperature for 2 h, concentrated under reduced pressure, neutralizedwith NH₃/MeOH and purified by prep-HPLC which gave 32 mg of4-(4-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)pyridazin-3-yl)-2-fluoro-5-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-oneas a yellow solid (46% yield).

Example 13: Splicing Assay (MAPTau, MADD, FOXM1

Various cells lines were treated with the SMSMs described herein. RNAwas then isolated, cDNA synthesized, qPCR performed and the levels ofvarious mRNA targets of the SMSMs were determined. In some instances,RNA was isolated, cDNA synthesized, qPCR performed and the levels ofmRNA isoforms in the various cell samples were determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/Primer Sequences:

FoxM1

FOXM1 A2 probe/primer: IDT DNA

(SEQ ID NO: 77) Primer 1: ACA GGT GGT GTT TGG TTA CA (SEQ ID NO: 78)Primer 2: AAA TTA AAC AAG CTG GTG ATG GG (SEQ ID NO: 79)Probe: /56-FAM/AG TTC TTT A/Zen/G TGG CGA TCT GCG  AGA /3IABkFQ/

(SEQ ID NO: 80) Primer 1: GAG CTT GCC CGC CAT AG (SEQ ID NO: 81)Primer 2: CTG GTC CTG CAG AAG AAA GAG (SEQ ID NO: 82) Probe:/5HEX/CC AAG GTG C/ZEN/T GCT AGC TGA GGA /3IABkFQ/

MADD

Isoform 4 (WT)

(SEQ ID NO: 83) Primer 1: GGC TAA ATA CTC TAA TGG AGA TTG TTA C(SEQ ID NO: 84) Primer 2: GGC TGT GTT TAA TGA CAG ATG AC (SEQ ID NO: 85)Probe: /5HEX/AG TGG TGA A/ZEN/G GAA ACA GGA GGG CGT TAG /3IABkFQ/Isoform 3 (Ex16)

(SEQ ID NO: 86) Primer 1: CAC TGT TGG GCT GTG TTT AAT G (SEQ ID NO: 87)Primer 2: ACA GTA CCA GCT TCA GTC TTT C (SEQ ID NO: 88) Probe:/56-FAM/TC TGA AAG G/ZEN/A AAC AGG AGG GCG TT/3IABkFQ/

MAPTau

MAPT Full length (4R) probe/primer: IDT DNA

(SEQ ID NO: 89) Primer 1: CCA TGC CAG ACC TGA AGA AT (SEQ ID NO: 90)Primer 2: TTG GAC TGG ACG TTG CTA AG (SEQ ID NO: 91) Probe:/5HEX/AA TTA TCT G/ZEN/C ACC TTC CCG CCT CC/3IABkFQ/MAPT Truncation (3R) Probe/Primer: IDT DNA

(SEQ ID NO: 92) Primer 1: AGA TCG GCT CCA CTG AGA A (SEQ ID NO: 93)Primer 2: GGT TTA TGA TGG ATG TTG CCT AAT G (SEQ ID NO: 94) Probe:/56-FAM/CA ACT GGT T/ZEN/T GTA GAC TAT TTG CAC CTT CCC /3IABkFQ/Cells:

Cells used included 93-T449, A-375, A-673, ASPC-1, BxPC-3, CCL-136,Daoy, DU-145, G-401, Hep-3B, IMR-32, K-562, LP-LoVo, MDA-MB-157,MDA-MB-231-luc, MDA-MB-468, MG-63, Ms751, NCI-H358, PACA-2, PANC-1,PC-3, RGX-MPC-11, RGX-PACA-2, SH-SY5Y, SJSA, SKOV3, SNU-16, SW872(HTB-92), TOLEDO, T.T, U-118, U-251MG, U-87MG, and Z-138 cells.

On the day of the experiment, a 96-well plate was seeded with the celllines of interest. The cells were diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells were added to eachwell (20,000 cells per well). The cells were treated with a compoundimmediately after plating.

The compounds were then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme was used. The stock compounds weremade at a concentration of 5 mM, and the DMSO concentration was set to0.2%. DMSO was used to normalize all the compound-containing wells andthe untreated cells.

The treated cells were incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates were placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA was isolated using the Cells to C_(T) kit (ThermoFisher, AM1728).The cells were washed once with 100 μL cold PBS. 50 μL of lysis bufferwas added to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction was mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution was added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes were incubated at room temperature for 2 minutes thenplaced on ice if the cDNA synthesis was to be performed immediately.Otherwise, the plates/tubes were stored at −80° C. cDNA synthesisreactions were then performed. Reverse Transcription (RT) Master mix wasprepared according to the table below.

Component Each reaction 2x RT Buffer 25 μL 20x RT Enzyme Mix 2.5 μLNuclease-free water 12.5 μL

40 μL RT master mix was added to PCR tubes or plate wells. 10 μL of RNAwas added to each tube/well. The RT thermal cycler program was then runand tubes or plate wells were incubated at 37° C. for 1 hour, then at95° C. for 5 minutes to deactivate the enzyme.

The qPCR was performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards were analyzed in triplicate. Cycle 1: 2minutes at 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40times): 15 seconds at 95° C., 1 minute at 60° C.

Isoform 1 or Isoform 2 Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xisoform 1 or isoform 2 probe/primer 0.5 μL Nuclease-free water 4.5 μLStandard DNA 5 μL

Unknown Sample (FOXM1 Isoform A2/FOXM1 Isoform BC Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xisoform 1 probe/primer 0.5 μL 40x isoform 2 probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA Standard Sample

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation)

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined isoform 2 and isoform 1 quantities were then be used todetermine the isoform 2: isoform 2 ratio at the various compoundconcentrations. The PPJA quantities were used in the normalization toaccount of cell proliferation effects of the compounds.

Standard Construction

PPIA Standard (5834 Bps)

G Block Sequence (JDT DNA)

(SEQ ID NO: 95) GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGT TCCCGCGGCCGC.FoxM1 A2 (5558 Bps)G Block Sequence (IDT DNA)

(SEQ ID NO: 96) GAATTCGTTTTTGGGGAACAGGTGGTGTTTGGTTACATGAGTAAGTTCTTTAGTGGCGATCTGCGAGATTTTGGTACACCCATCACCAGCTTGTTTAATTTTATCTTTCTTTGTTTATCAGCGGCCGCFoxM2 BC (6439 Bps)G Block Sequence (IDT DNA)

(SEQ ID NO: 97) GAATTCGGCGGAAGATGAAGCCACTGCTACCACGGGTCAGCTCATACCTGGTACCTATCCAGTTCCCGGTGAACCAGTCACTGGTGTTGCAGCCCTCGGTGAAGGTGCCATTGCCCCTGGCGGCTTCCCTCATGAGCTCAGAGCTTGCCCGCCATAGCAAGCGAGTCCGCATTGCCCCCAAGGTGCTGCTAGCTGAGGAGGGGATAGCTCCTCTTTCTTCTGCAGGACCAGGGAAAGAGGAGAAACTCCTGTTTGGAGAAGGGTTTTCTCCTTTGCTTCCAGTTCAGACTATCAAGGAGGAAGAAATCCAGCCTGGGGAGGAAATGCCACACTTAGCGAGACCCATCAAAGTGGAGAGCCCTCCCTTGGAAGAGTGGCCCTCCCCGGCCCCATCTTTCAAAGAGGAATCATCTCACTCCTGGGAGGATTCGTCCCAATCTCCCACCCCAAGACCCAAGAAGTCCTACAGTGGGCTTAGGTCCCCAACCCGGTGTGTCTCGGAAATGCTTGTGATTCAACACAGGGAGAGGAGGGAGAGGAGCCGGTCTCGGAGGAAACAGCATCTACTGCCTCCCTGTGTGGATGAGCCGGAGCTGCTCTTCTCAGAGGGGCCCAGTACTTCCCGCTGGGCCGCAGAGCTCCCGTTCCCAGCAGACTCCTCTGACCCTGCCTCCCAGCTCAGCTACTCCCAGGAAGTGGGAGGACCTTTTAAGACACCCATTAAGGAAACGCTGCCCATCTCCTCCACCCCGAGCAAATCTGTCCTCCCCAGAACCCCTGAATCCTGGAGGCTCACGCCCCCAGCCAAAGTAGGGGGACTGGATTTCAGCCCAGTACAAACCTCCCAGGGTGCCTCTGACCCCTTGCCTGACCCCCTGGGGCTGATGGATCTCAGCACCACTCCCTTGCAAAGTGCTCCCCCCCTTGAATCACCGCAAAGGCTCCTCAGTTCAGAACCCTTAGACCTCATCTCCGTCCCCTTTGGCAACTCTTCTCCCTC AGCGGCCGCMADD Isoform 4 (WT) (5668 Bps)G Block Sequence (IDT DNA)

(SEQ ID NO: 98) GAATTCAAAGGTGCCCGAGAGAAGGCCACGCCCTTCCCCAGTCTGAAAGTATTTGGGCTAAATACTCTAATGGAGATTGTTACTGAAGCCGGCCCCGGGAGTGGTGAAGGAAACAGGAGGGCGTTAGTGGATCAGAAGTCATCTGTCATTAAACACAGCCCAACAGTGAAAAGAGAACCTCCATCACCCCAGGGTCGATCCAGCAATTCTAGTGAGAACCAGCAGTTCCTGCGGCCGCMADD Isoform 3 (Ex16) (5689 Bps)G Block Sequence (IDT DNA) IDC-959 DNA

(SEQ ID NO: 99) GAATTCACCGAGGGCTTCGGGGGCATCATGTCTTTTGCCAGCAGCCTCTATCGGAACCACAGTACCAGCTTCAGTCTTTCAAACCTCACACTGCCCACCAAAGGTGCCCGAGAGAAGGCCACGCCCTTCCCCAGTCTGAAAGGAAACAGGAGGGCGTTAGTGGATCAGAAGTCATCTGTCATTAAACACAGCCCAACAGTGAAAAGAGAACCTCCATCACCCCAGGGTCGATCCAGCAATTCTAG TGAGAAGCGGCCGCMAPTau Full Length (4R) (5654 Bps)G Block Sequence (IDT DNA)

(SEQ ID NO: 100) GAATTCTCCGCCAAGAGCCGCCTGCAGACAGCCCCCGTGCCCATGCCAGACCTGAAGAATGTCAAGTCCAAGATCGGCTCCACTGAGAACCTGAAGCACCAGCCGGGAGGCGGGAAGGTGCAGATAATTAATAAGAAGCTGGATCTTAGCAACGTCCAGTCCAAGTGTGGCTCAAAGGATAATATCAAACACGTCCCGGGAGGCGGCAGTGTGCAAGCGGCCGCMAPTau Truncation (3R) (5644 Bps)G Block Sequence (IDT DNA)

(SEQ ID NO: 101) GAATTCTCAAGTCCAAGATCGGCTCCACTGAGAACCTGAAGCACCAGCCGGGAGGCGGGAAGGTGCAAATAGTCTACAAACCAGTTGACCTGAGCAAGGTGACCTCCAAGTGTGGCTCATTAGGCAACATCCATCATAAACCAGGAGGTGGCCAGGTGGAAGTAAAATCTGAGAAGCTTGACTTCAAGGACAGAGT CCAGTCGAAGGCGGCCGC

The G Blocks were inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids were then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution necessary to make the top standard is calculated. A topconcentration 200,000,000 copies/μL of the stock plasmid was prepared inTE buffer. A series of 10-fold dilutions, also in TE, were then made. Atotal of 5 μL of each standard was used in a qPCR well to generatesamples containing 109 copies, 108 copies, 10⁷copies, 10⁶ copies, 10⁵copies, 10⁴ copies, 10³ copies, 10² copies, 10¹copies, and 0 copies.

An assay to measure the FOXM1^(A2) mRNA and FOXM1^(BC) mRNA, orMADD^(WT (isoform 4)) mRNA and MADD^(Ex16 (isoform 3)) mRNA, orMAPTau^(4R) mRNA and MAPTau^(3R) mRNA simultaneously in cell wells wasperformed. The RNA values were measured relative to DMSO control andalso included a housekeeping gene, PPIA to ensure data was consistent.The mRNA values were measured after 24 hours of incubation with the SMSMcompounds. The SMSMs dose dependently increased FOXM1^(A2) levels whileconcomitantly decreasing FOXM1^(BC) levels with EC₅₀ and IC₅₀ values inthe nanomolar range. This assay was performed in the cell lines shown inTable 3A. Exemplary FOXM1 results are shown in Table 3A.

TABLE 3A FOXM1 Cell Line SMSM-129 SMSM-138 SMSM-223 SMSM-167 SMSM-151SMSM-191 SMSM-168 SMSM-160 A-375 <1 1-10  11-100 <1 1-10 1-10 1-10 <1A-673 <1 11-100 — <1 1-10 <1 1-10 1-10 BxPC-3 — 101-200  200-500 — — — —11-100 Daoy — 11-100 101-200 — — — — — DU-145 — 11-100 200-500 — — — — —G-401 — 101-200   11-100 — — — — — Hep-3B — — — 11-100 101-200  —101-200  — K-562 — — — 1-10 11-100 1-10 11-100 — LP-LoVo 1-10 — — — — —— — MDA-MB-157 <1 — — — — — — — MDA-MB-231-luc <1 11-100 — — — — —11-100 MDA-MB-468 — — — 1-10 11-100 1-10 11-100 — NCI-H358 — — — <1 1-101-10 1-10 — PANC-1 — — — 11-100 101-200  101-200  101-200  — PC-3 — — —11-100 11-100 11-100 11-100 — SH-SY5Y — 11-100  11-100 — — — — — SKOV31-10 — T.T 11-100 101-200 — — — — — U-118 11-100 — — — — — 1-10 U-87MG —11-100 11-100 11-100 11-100 — Z-138 <1 11-100 — — — — — 1-10

Example 14: SMN2 Splicing Assay—Monitoring Expression Levels of SMN2Splice Variant Using Real-Time Quantitative PCR

Various cells lines were treated with the SMSMs described herein. RNAwas then isolated, cDNA synthesized, qPCR performed and the levels ofvarious mRNA targets of the SMSMs were determined. In some instances,RNA was isolated, cDNA synthesized, qPCR performed and the levels ofmRNA isoforms in the various cell samples were determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/Primer Sequences:

The table below summarizes the primers used.

Sequence 5'- Spe- (5'-3') Primer Primer Mod. 3'-Mod. cies GCT CAC ATT FL  0.04  None None Human CCT TAA ATT Forward μmol AAG GAG AAA Primer(SEQ ID NO: 102) TGG CTA TCA  Δ7  0.04  None None Human TAC TGG CTA  Forward μmol TTA TAT GGA A Primer (SEQ ID NO: 103) TCC AGA TCT  Reverse 0.04  None None Human GTC TGA TCG Primer μmol TTT CTT (SEQ ID NO: 104)CTG GCA TAG  Probe 0.2  FAM BHQ-1 Human AGC AGC ACT μmol (Fluo-AAA TGA CAC  rescein) CAC (SEQ ID NO: 105)

Cells:

SMA Type I Patient Cells (GM03813 (Coriell))

Protocol

On the day of the experiment, a 96-well plate was seeded with the celllines of interest. The cells were diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells were added to eachwell (20,000 cells per well). The cells were treated with a compoundimmediately after plating.

The compounds were then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme was used. The stock compounds weremade at a concentration of 5 mM, and the DMSO concentration was set to0.2%. DMSO was used to normalize all the compound-containing wells andthe untreated cells.

The treated cells were incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates were placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA was isolated using the Cells to C_(T) kit (ThermoFisher, AM1728).The cells were washed once with 100 μL cold PBS. 50 μL of lysis bufferwas added to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction was mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution was added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes were incubated at room temperature for 2 minutes thenplaced on ice if the cDNA synthesis was to be performed immediately.Otherwise, the plates/tubes were stored at −80° C.

cDNA synthesis reactions were then performed. 40 μL RT master mix wasadded to PCR tubes or plate wells. 10 μL of RNA was added to eachtube/well. The RT thermal cycler program was then run and tubes or platewells were incubated at 37° C. for 1 hour, then at 95° C. for 5 minutesto deactivate the enzyme.

The qPCR was performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards were analyzed in triplicate. Cycle 1: 2minutes at 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40times): 15 seconds at 95° C., 1 minute at 60° C.

SMN2^(FL) or SMN2^(Δ7) Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xSMN2^(FL) or SMN2^(Δ7) probe/primer 0.5 μL Nuclease-free water 4.5 μLStandard DNA 5 μL

Unknown Sample (Foxm1 Isoform A2/Foxm1 Isoform BC Quantitation

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xSMN2^(FL) probe/primer 0.5 μL 40x SMN2^(Δ7) probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA Standard Sample

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined SMN2^(Δ7) and SMN2^(FL) quantities were then be used todetermine the SMN2^(Δ7):SMN2^(FL) ratio at the various compoundconcentrations. The PPIA quantities were used in the normalization toaccount of cell proliferation effects of the compounds.

Standard Construction

PPIA Standard (5834 Bps)

G Block Sequence (IDT DNA)

(SEQ ID NO: 95) GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGT TCCCGCGGCCGCSMN2^(FL) Standard G Block Sequence (IDT DNA) were UsedSMN2^(Δ7) Standard G Block Sequence (IDT DNA) were Used

The G Blocks were inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids were then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution to make the top standard was calculated. A topconcentration 200,000,000 copies/μL of the stock plasmid was prepared inTE buffer. A series of 10-fold dilutions, also in TE, were then made. Atotal of 5 μL of each standard was used in a qPCR well to generatesamples containing 109 copies, 10⁸ copies, 10⁷ copies, 10⁶ copies, 10⁵copies, 10⁴ copies, 10¹ copies, 10² copies, 10¹ copies, and 0 copies.

An assay to measure the SMN2^(FL) mRNA and SMN2^(Δ7) mRNA simultaneouslyin cell wells was performed. The RNA values were measured relative toDMSO control and also included a housekeeping gene, PPIA to ensure datawas consistent. The mRNA values were measured after 24 hours ofincubation with the SMSM compounds. The SMSMs dose dependently increasedthe SMN2^(FL) values while concomitantly decreasing the SMN2^(Δ7) valuesat the same with EC₅₀ and IC₅₀ values in the nanomolar range.

Additionally, to monitor expression levels of SMN2 splice variant usingreal-time quantitative PCR, SMA type I patient cells (GM03813 (Coriell))were plated at 5,000 cells/well in 200 μl Dulbecco's modified Eagle'smedium (DMEM) with GlutaMAX and 10% fetal bovine serum (FBS) (LifeTechnologies, Inc.) in 96-well plates, and incubated for 6 hours in acell culture incubator. Cells were then treated with SMSMs at differentconcentrations (0.5% DMSO) in duplicate for 24 hours. After removal ofthe supernatant, cells were lysed in Cells-To-Ct lysis buffer (LifeTechnologies, Inc.) according to the manufacturer's recommendations. ThemRNA levels of SMN2 FL, SMN2 Δ7 were quantified using Taqman-basedRT-qPCR and SMN2-specific primers and probes. The SMN2 forward andreverse primers were each used at a final concentration of 0.4 μM. TheSMN2 probe was used at a final concentration of 0.15 M. RT-qPCR wascarried out at the following temperatures for indicated times: Step 1:48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15 sec); Step4: 60° C. (1 min); Steps 3 and 4 were repeated for 40 cycles. The Ctvalues for each mRNA were converted to mRNA abundance using actual PCRefficiencies.

Exemplary results of the assays described in the examples above areshown in Table 3B.

TABLE 3B SMSM# GM03813^(FL) EC₅₀ (nM) GM03813^(Δ7) IC₅₀ (nM) 138 1 1 1600.6 0.7 151 0.7 0.9 289 4 4

Example 15: IKBKAP Splicing Assay

Various cells lines were treated with the SMSMs described herein. RNAwas then isolated, cDNA synthesized, qPCR performed and the levels ofIKBKAP targets of the SMSMs were determined.

Materials

Cells to Ct kit: ThermoFisher, AM1728. TaqMan Gene Expression MasterMix: ThermoFisher, 4369542. PPIA probe/primer: ThermoFisher,Hs03045993_gH, VIC-MGB_PL.

Probe/Primer Sequences:

IKBKAP

IKBKAP WT Probe/Primer: IDT DNA

(SEQ ID NO: 106) Primer 1: ACC AGG GCT CGA TGA TGA A (SEQ ID NO: 107)Primer 2: GCA GCA ATC ATG TGT CCC A (SEQ ID NO: 108)Probe: /56-FAM/GT TCA CGG A/ZEN/T TGT CAC TGT TGT  GCC /3IABkFQ/IKBKAP MU Probe/Primer: IDT DNA

(SEQ ID NO: 109) Primer 1: GAA GGT TTC CAC ATT TCC AAG (SEQ ID NO: 110)Primer 2: CAC AAA GCT TGT ATT ACA GAC T (SEQ ID NO: 111) Probe:/5HEX/CT CAA TCT G/ZEN/A TTT ATG ATC ATA ACC CTA  AGG TG/3IABkFQ/Protocol

On the day of the experiment, a 96-well plate was seeded with the celllines of interest. The cells were diluted with full growth media to aconcentration of 2.0×10⁵ cells/mL and 100 μL of cells were added to eachwell (20,000 cells per well). The cells were treated with a compoundimmediately after plating.

The compounds were then added to the cell plate using the HP compounddispenser. In the initial experiment, a top concentration of 10 μM andan 8 point 4-fold dilution scheme was used. The stock compounds weremade at a concentration of 5 mM, and the DMSO concentration was set to0.2%. DMSO was used to normalize all the compound-containing wells andthe untreated cells.

The treated cells were incubated at 37° C. in a 5% CO₂ incubator for thedesired amount of time. Plates were placed in a plastic bag with a wetpaper towel to prevent evaporation.

RNA was isolated using the Cells to C_(T) kit (ThermoFisher, AM1728).The cells were washed once with 100 μL cold PBS. 50 μL of lysis bufferwas added to each well/tube (49.5 μL lysis buffer+0.5 μL DNase I perwell/tube). The lysis reaction was mixed and incubated at roomtemperature for 5 minutes. 5 μL of stop solution was added directly intoeach cell lysis reaction and mixed by pipetting up and down 5 times. Theplates/tubes were incubated at room temperature for 2 minutes thenplaced on ice if the cDNA synthesis was to be performed immediately.Otherwise, the plates/tubes were stored at −80° C.

cDNA synthesis reactions were then performed. 40 μL RT master mix wasadded to PCR tubes or plate wells. 10 μL of RNA was added to eachtube/well. The RT thermal cycler program was then run and tubes or platewells were incubated at 37° C. for 1 hour, then at 95° C. for 5 minutesto deactivate the enzyme.

The qPCR was performed using a QuantStudio 6 instrument (ThermoFisher)and the following cycling conditions and according to the tables below.All samples and standards were analyzed in triplicate. Cycle 1: 2minutes at 50° C. Cycle 2: 10 minutes at 95° C. Cycle 3 (repeat 40times): 15 seconds at 95° C., 1 minute at 60° C.

IKBKAP^(FL) or IKBKAP^(Δ20) Standard Samples

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xIKBKAP^(FL) or IKBKAP^(Δ20) probe/primer 0.5 μL Nuclease-free water 4.5μL Standard DNA 5 μL

Unknown sample (IKBKAP^(FL)/IBKAP^(Δ20) quantitation

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 40xIKBKAP^(FL) probe/primer 0.5 μL 40x IKBKAP^(Δ20) probe/primer 0.5 μLNuclease-free water 5 μL Sample DNA 4 μL

PPIA STANDARD SAMPLE

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 4.67 μL Standard DNA 5 μL

Unknown Sample (PPIA Quantitation

Component Per qPCR well 2x TaqMan Gene Expression Master Mix 10 μL 60xPPIA probe/primer 0.33 μL Nuclease-free water 5.67 μL Sample DNA 4 μL

The determined IKBKAP^(FL) and IKBKAP^(Δ21) isoform quantities were thenused to determine the IKBKAP^(FL): IKBKAP^(Δ20) ratio at increasing SMSMcompound concentrations. The PPIA quantities were used in thenormalization to account of cell proliferation effects of the compounds.

Standard Construction

PPIA Standard (5834 Bps)

G Block Sequence (IDT DNA IDC-937 DNA

(SEQ ID NO: 95) GAATTCGGCCAGGCTCGTGCCGTTTTGCAGACGCCACCGCCGAGGAAAACCGTGTACTATTAGCCATGGTCAACCCCACCGTGTTCTTCGACATTGCCGTCGACGGCGAGCCCTTGGGCCGCGTCTCCTTTGAGCTGTTTGCAGACAAGGTCCCAAAGACAGCAGAAAATTTTCGTGCTCTGAGCACTGGAGAGAAAGGATTTGGTTATAAGGGTTCCTGCTTTCACAGAATTATTCCAGGGTTTATGTGTCAGGGTGGTGACTTCACACGCCATAATGGCACTGGTGGCAAGTCCATCTATGGGGAGAAATTTGAAGATGAGAACTTCATCCTAAAGCATACGGGTCCTGGCATCTTGTCCATGGCAAATGCTGGACCCAACACAAATGGT TCCCGCGGCCGCIkbkap Wt (5639 Bps)

(SEQ ID NO: 112) GAATTCCTTCATTTAAAACATTACAGGCCGGCCTGAGCAGCAATCATGTGTCCCATGGGGAAGTTCTGCGGAAAGTGGAGAGGGGTTCACGGATTGTCACTGTTGTGCCCCAGGACACAAAGCTTGTATTACAGATGCCAAGGGGAAACTTAGAAGTTGTTCATCATCGAGCCCTGGTTTTAGCTCAGATTCGGAA GTGGTGCGGCCGCIkbkap Mu (5645 Bps)

(SEQ ID NO: 113) GAATTCCGGATTGTCACTGTTGTGCCCCAGGACACAAAGCTTGTATTACAGACTTATGTTTAAAGAGGCATTTGAATGCATGAGAAAGCTGAGAATCAATCTCAATCTGATTTATGATCATAACCCTAAGGTGTTTCTTGGAAATGTGGAAACCTTCATTAAACAGATAGATTCTGTGAATCATATTAACTTGTTT TTTACAGAATTGCGGCCGC

The G Blocks were inserted into the pCI-neo mammalian expression vector(Promega) at the EcoRI and NotI restriction sites (bolded) usingInfusion cloning technology (Clontech). The plasmids were then purifiedusing standard miniprep or maxiprep kits (Macherey Nagel).

Standard Curve Preparation

The dilution necessary to make the top standard is calculated. A topconcentration 200,000,000 copies/μL of the stock plasmid was prepared inTE buffer. A series of 10-fold dilutions, also in TE, were then made. Atotal of 5 μL of each standard was used in a qPCR well to generatesamples containing 10⁹ copies, 10⁸ copies, 10⁷ copies, 10⁶ copies, 10⁵copies, 10⁴ copies, 10³ copies, 10² copies, 10¹ copies, and 0 copies.

An assay to measure the IKBKAP^(FL) mRNA and IKBKAP^(Δ20) mRNAsimultaneously in cell wells was performed. The RNA values were measuredrelative to DMSO control and also included a housekeeping gene, PPIA toensure data was consistent. The mRNA values were measured after 24 hoursof incubation with the SMSM compounds. The SMSMs dose dependentlyincreased the IKBKAP^(FL) values while concomitantly decreasing theIKBKAP¹²¹ values at the same with EC₅₀ and IC₅₀ values in the nanomolarrange.

Exemplary results of the assays are shown in Table 3C:

TABLE 3C SMSM# IKBKAP^(FL) EC₅₀ (nM) IKBKAP^(Δ20) IC₅₀ (nM) 266 <100 <200 162 — 201-1000 138 101-350 201-1000 152  351-1000 >1000 217 351-1000 201-1000 315 >1000  >1000 160 <100  <200 161 <100  <200 223101-350 >1000 238 101-350 201-1000 154  351-1000 — 278 101-350  <200 282101-350 201-1000 218  351-1000 >1000 228  351-1000 >1000 240 101-350201-1000

Example 16: Cell Viability and Proliferation

Small molecule splicing modulators were tested in a dose-response assayusing different cancer cell lines. Cells were first plated in 96-wellplastic tissue culture plates (10,000 cells per well). The cells weretreated with 500 nM of SMSM or vehicle alone (DMSO) for 48 hours.Following treatment, the cells were washed with PBS, stained with acrystal violet staining solution, and allowed to dry for 48-72 hrs.After drying, sodium citrate buffer was added to each well and allowedto incubate for 5 min at room temperature. The absorbance was measuredat 450 nM using a microplate reader (Biorad; Hercules, Calif.). Therelative cell proliferation for each of the cancer cell lines wasdetermined.

To measure cell viability, cells were plated in 96-well plastic tissueculture plates at a density of 5×10³ cells/well. Twenty-four hours afterplating, cells were treated with various SMSMs. After 72 hours, the cellculture media were removed and plates were stained with 100 mL/well of asolution containing 0.5% crystal violet and 25% methanol, rinsed withdeionized water, dried overnight, and resuspended in 100 mL citratebuffer (0.1 M sodium citrate in 50% ethanol) to assess platingefficiency. Intensity of crystal violet staining, assessed at 570 nm andquantified using a Vmax Kinetic Microplate Reader and Softmax software(Molecular Devices Corp., Menlo Park, Calif.), were directlyproportional to cell number. Data were normalized to vehicle-treatedcells and were presented as the mean±SE from representative experiments.SMSMs that are effective were determined for various cells lines.

Small molecule splicing modulators were tested in a dose-response assayusing A673 cells and NHDF cells.

A673 cells or NHDF cells were first plated in 96-well plastic tissueculture plates (10,000 cells per well). The cells were treated withvehicle alone (DMSO), or increasing concentrations of SMSM compounds for72 h. Following treatment, cell proliferation was determined using acrystal violet assay. The relative cell proliferation at eachconcentration was determined.

Exemplary results are shown in the table below and FIGS. 9A-9H.

Ratio SMSM#/drug NHDF/A673 IC₅₀ 160 >225 151 >350 167 >2,500 168 >500Panobinostat ≤10 Belinostat ≤10 Vorinostat ≤10 Mocetinostat ≤10Trichostatin A ≤10

Example 17: Monitoring Expression Levels of FOXM1 Splice Variants UsingReal-Time Quantitative PCR

Human fibroblasts were plated at 10,000 cells/well in 200 μL DMEM withGlutaMAX and 10% FBS in 96-well plates in a cell culture incubator (37°C., 5% CO₂, 100% relative humidity). Cells were then treated with SMSMsin Table 1B at different concentrations (0.1-1000 nM, each in 0.5% DMSO)in triplicate for 24 hours. RNA extraction was performed as perinstructions in the Cells-to-CT™ Kits (Ambion®, Applied Biosystems). RNAsamples were frozen at −20° C. until further analysis. Relativeexpression levels of full-length FOXM1 (FOXM1^(FL)) or FOXM1 lackingexon VIIa (FOXM1^(ΔVIIaI)) with GAPDH for internal control, was measuredusing one-step multiplex reverse transcription-polymerase chain reaction(RT-PCR). TaqMan® FAM probes were used for relative quantitation ofFOXM1^(FL) or FOXM1^(ΔVIIa) expression levels and TaqMan® VIC probeswere used for relative quantitation of human GAPDH levels. The fidelityof the amplification methods was determined using the ΔΔCt relativequantification method for quantitative PCR. The data shows that thecompounds induced alternative splicing of FOXM1 towards full-lengthFOXM1. The SMSMs increased expression of the FOXM1^(FL) mRNA.Correspondingly, the mRNAs for FOXM1^(ΔVIIa) declined. The datademonstrate that upregulation of FOXM1^(FL) with downregulation ofFOXM1^(ΔVIIa) by treatment with the SMSMs of the present disclosure weredirectly correlated, indicating an effect of the SMSMs on alternativesplicing of FOXM1. The resulting concentration dependence curves of theFOXM1^(ΔVIIa) splice variant are fitted to a Hill binding equation toyield IC₅₀ values. Taken together, the data underline a splicingmodifying activity in the FOXM1 gene. This may result in arrest of cellcycle and induction of apoptosis, as the FOXM1^(FL) variant created bySMSM treatment is functionally inactive, and antagonizes thepro-proliferating. effect of functional FOXM1.

Exemplary results are shown in FIG. 7 and FIG. 12.

Example 18: Maximum Tolerable Dose Study

Survival of mice after administration of SMSMs after 10 or 11 days wasassessed.

Tolerance of the drug treatments was determined by measuring the weightof the mice during the period of drug administration. Body weight wasmeasured prior to tumor inoculation and prior to the treatmentadministration and then daily. The changes in the final weight of themice for the SMSM treatments were determined. Results are summarized inthe table below:

Group Route of Treatment Group Adminis- Dose Dosing (3 per group) #Outcome tration (mg/kg) Schedule Vehicle 1 All survived IP NA QDx11SMSM-151 2 All survived IP 1 QDx11 Vehicle 3 All survived PO NA QDx11SMSM-151 4 All survived PO 10  QDx11 SMSM-151 5 All survived PO 10 BIDx11 Vehicle 1 All survived IP NA QDx12 SMSM-167 2 All survived IP 1QDx12 SMSM-167 3 All survived IP   0.1 BIDx12 SMSM-167 4 All survived IP  0.3 BIDx12 Vehicle 5 All survived PO NA QDx12 SMSM-167 6 All survivedPO 5 QDx12 SMSM-167 7 BW loss in PO 5 BIDx12 one animal

Example 19: Dose Range and Time Course Studies

Dose range and time course studies comparing anti-neoplastic effects ofSMSM-167 and SMSM-151 against vehicle were conducted.

Experimental groups used for this study are shown in the table below andFIGS. 14A-C.

Route of Group Dose Dosing Adminis- # Group Treatment (mg/kg) Scheduletration Mice 1 Vehicle NA QDx14 PO 10 2 SMSM-151 3 mg/kg BIDx14 IP 10 3SMSM-167 5 mg/kg BIDx14 PO 10 4 SMSM-167 7.5 mg/kg BIDx14 PO 10 5SMSM-167 10 mg/kg QDx14 PO 10

Female NCrNu mice were used. Age range of enrolment was 7-10 weeks. Atotal of 75 animals were for the studies.

The A673 tumor cell line was maintained in vitro as a monolayer culture.The tumor cells were routinely subcultured twice weekly by TryplE, anddid not to exceed 4-5 passages. The cells growing in an exponentialgrowth phase were harvested and counted for tumor inoculation.

Each mouse were inoculated into a right flank with the single cellsuspension of 95% viable tumor cells (5×10⁶ cells/mouse) in serum-freeRPMJ 1640 Media for tumor development. Treatments were administered whenmean tumor size reached approximately 75 mm³.

An acclimation period of a minimum of 72 hrs was allowed between animalreceipt and tumor inoculation in order to accustom the animals to thelaboratory environment. Immunodeficient NCrNu mice were maintained in apathogen-free environmnent. Animals were fed a diet of Irradiated Mousepellet feed Purina rodent diet #5053 (Fisher Feeds, Bound Brook, N.J.)and chlorinated water from a reverse osmosis (RO) system (4-6 ppm).

Before commencement of treatment, all animals were weighed and assignedto treatment groups using a randomization procedure. Mice wererandomized into groups based upon their tumor sizes to ensure that eachgroup had approximately the same mean tumor size and range of tumorsize.

After inoculation, the animals were checked daily for morbidity andmortality. At the time of routine monitoring, the animals were checkedfor any effects of tumor growth on normal behavior such as mobility,food and water consumption, body weight gain/loss, eye/hair matting andany other abnormal effects. Deaths and observed clinical signs wererecorded. Animals that were observed to be in a continuing deterioratingcondition or bearing a tumor exceeding 2,000 mm³ in size wereeuthanized.

Body weight were measured prior to tumor inoculation and prior to thetreatment administration and then daily. Tumor size were measured 2-3times per week in two dimensions using a caliper, and the volume wereexpressed in mm³ using the formula: V=0.5×a×b² where a and b are thelong and short diameters of the tumor, respectively.

Studies were terminated when the tumor size in the vehicle treated groupreached 2,000 mm³. Each mouse was bled at 2 hrs after the last dose andat least 50 μl of plasma were collected from each mouse. All of thecollected plasma samples and retainer dosing solutions for each doselevel were used for bioanalytical measurements. All tumors were alsocollected and weighed. One necrosis-free tumor fragment of approximately50 mg was taken from each tumor and flash-frozen for RNA isolation. Theremaining tumor was flash frozen for PK analysis.

Example 20: Subcutaneous U87-Luc Brain Tumor Model in Ncr Nude Mice

The efficacy of SMSM-167, SMSM-160 and SMSM-151 in a subcutaneousU87-Luc brain tumor model in C.B-17 SCID mice was assessed.

Experimental groups to be used for this study are shown in the tablebelow and FIGS. 15A-B.

Route of # Group Dose Dosing Adminis- Mice/ Group Treatment (mg/kg)Schedule tration Group 1 Vehicle — BIDx14 PO 10 2 SMSM-160 1.5 mg/kgBIDx14 IP 10 3 SMSM-151 10 mg/kg BIDx14 PO 10 4 SMSM-167 5 mg/kg BIDx14PO 10

Tumor inoculation began on day 0. Treatments were administered when meantumor size reached approximately 100 mm³. 100 mice were used for thisstudy.

An acclimation period of a minimum of 72 hrs was allowed between animalreceipt and tumor inoculation in order to accustom the animals to thelaboratory environment. Animals were fed a diet of Irradiated Mousepellet feed Purina rodent diet #5053 (Fisher Feeds, Bound Brook, N.J.)and chlorinated water from a reverse osmosis (RO) system (4-6 ppm).

Before commencement of treatment, all animals were weighed and assignedto treatment groups using a randomization procedure. Mice wererandomized into groups based upon their tumor sizes, as measured bycaliper to ensure that each group had approximately the same mean tumorsize and range of tumor size.

After inoculation, the animals were checked daily for morbidity andmortality. At the time of routine monitoring, the animals were checkedfor any effects of tumor growth on normal behavior such as mobility,food and water consumption, body weight gain/loss, eye/hair matting andany other abnormal effects. Deaths and observed clinical signs wererecorded. Animals that were observed to be in a continuing deterioratingcondition or bearing a tumor exceeding 2,000 mm³ in size wereeuthanized.

Body weight was measured prior to tumor inoculation and prior to thetreatment administration and then daily. Tumor size was measured 2 timesper week in two dimensions using a caliper. Studies were terminated whenthe tumor size in the vehicle treated group reached 2,000 mm³. Eachmouse was bled at 2 hrs after the last dose and at least 50 μl of plasmawas collected from each mouse. All of the collected plasma samples andretainer dosing solutions for each dose level were used forbioanalytical measurements. All tumors were also collected and weighed.One necrosis-free tumor fragment of approximately 50 mg was taken fromeach tumor and flash-frozen for RNA isolation. The remaining tumor wasflash frozen for PK analysis.

Example 21: In Vivo SMSM Treatment Inhibits Tumor Growth

Studies were performed to assess the effects of in vivo SMSM treatmenton glioblastoma, breast, pancreatic, prostate, melanoma, lymphoma andEwing sarcoma tumors. Studies were also performed to assess the effectsof in vivo SMSM treatment on mRNA levels. Immunocompromised nude micewith pre-existing glioblastoma, breast, pancreatic, prostate, melanoma,lymphoma and Ewing sarcoma xenografts were treated with vehicle orSMSMs. Tumor tissues from subcutaneous xenografts were broken into apowder using a BioPulverizer (Biospec Products, Inc.). After SMSMtreatment, mRNA was isolated from the xenografts and was analyzed byqRT-PCR.

Tumor size was measured 2 times per week in two dimensions using acaliper. Studies were terminated when the tumor size in the vehicletreated group reached 2,000 mm³. Each mouse was bled at 2 hrs after thelast dose and at least 50 μl of plasma was collected from each mouse.All of the collected plasma samples and retainer dosing solutions foreach dose level were used for bioanalytical measurements. All tumorswere also collected and weighed. One necrosis-free tumor fragment ofapproximately 50 mg was taken from each tumor and flash-frozen for RNAisolation. The remaining tumor was flash frozen for PK analysis.

The effects of in vivo SMSM treatments on pre-existing subcutaneousglioblastoma, breast, pancreatic, prostate, melanoma, lymphoma and Ewingsarcoma xenografts were assessed. For these in vivo experiments, 1×10⁶Raji, A375, A673, MDA-MB-231, BxPC-3, PC-3 or U87 (cells re-suspended in100 μl PBS were subcutaneously injected into the flanks of nude mice.When the tumor reached approximately 100 mm³(volume=(¾)(π)(length/2)(width/2)²), the treatments indicated in thetables below were initiated.

As shown in the table below and FIGS. 14A, 14B and 14C, SMSM-160treatment of immunocompromised nude mice with pre-existing A673xenografts led to tumor growth inhibition (TGI). (TGI(%)=(1−(TV_(Treatment/Dx)−TV_(Treatment/D1))/(TV_(Control/Dx)−TV_(Control/D1)))×100).

TGI(%) Group Day 7 Day 11 Day 14 Day 18 SMSM-167 1 65.56% 56.92% 55.14%59.68% 5 mg/kg BID PO SMSM-167 2 59.45% 64.75% 64.43% 72.80% 7.5 mg/kgBID PO SMSM-167 3 −32.72% 3.85% −2.13% 41.77% 10 mg/kg QD PO

As shown in the table below and FIGS. 16A, 16B and 16C, SMSM-160treatment of immunocompromised nude mice with pre-existing A673xenografts led to tumor growth inhibition (TGI). (TGI(%)=(1−(TV_(Treatment/Dx)−TV_(Treatment/D1))/TV_(Control/Dx)−TV_(Control/D1)))×100).

Tumor Growth Inhibition (TGI) (%) Group Day 3 Day 6 Day 10 Day 13SMSM-160; 1 mg/kg; BID 2 −0.94% 25.67% 25.67% 42.90%

As shown in the table below and FIGS. 17A and 17B, SMSM-160 treatment ofimmunocompromised nude mice with pre-existing A375 xenografts led totumor growth inhibition (TGI).

Tumor Growth Inhibition (TGI) (%) Group D 4 D 6 D 10 D 13 D 17 D 21Vemurafenib; 50 mg/kg; p.o.; 9.47% 9.98% 24.32% 50.53% 69.66% 82.03% BIDSMSM-160; 3 mg/kg; ip.; QD 3.40% 47.56% 44.13% 40.08% 45.12% 53.98%SMSM-160; 3 mg/kg; ip.; BID 33.09% 92.99% 109.59% 105.98% 99.59% 94.68%SMSM-160; 10 mg/kg; ip.; 72.84% 118.42% 112.78% 103.12% 97.84% 95.59%QD*5 day

As shown in the table below and FIGS. 20A and 20B, SMSM-151 treatment ofimmunocompromised nude mice with pre-existing A673 xenografts led totumor growth inhibition (TGI).

Tumor Growth Inhibition (TGI) (%) Group Day 3 Day 6 Day 10 Day 13SMSM-151 28.03% 34.29% 22.09% 30.12% 10 mg/kg BID p.o. SMSM-151 37.61%45.97% 55.24% 71.29% 20 mg/kg BID p.o. SMSM-151 23.90% 34.28% 17.11%23.52% 30 mg/kg QD p.o.

As shown in the table below and FIGS. 21A and 21B, SMSM-160 or SMSM-151treatment of immunocompromised nude mice with pre-existing A-375xenografts led to tumor growth inhibition (TGI).

Tumor Growth Inhibition (TGI) (%) Group D 4 D 7 D 11 D 14 D 18 D 21Vemurafenib, 111.22% 112.77% 114.44% 109.55% 107.72% 106.56% 50 mg/kg,p.o., BID *21 days SMSM-160 3.60% 18.11% 30.05% 30.28% 42.80% 37.88% 1.5mg/kg, i.p., BID *21 days SMSM-160 38.68% 46.64% 94.46% 89.78% 81.80%71.33% 3 mg/kg, i.p., BID *21 days SMSM-151 21.81% 13.08% 24.17% 34.70%39.27% 36.89% 1.5 mg/kg, i.p., BID *21 days SMSM-151 15.21% 18.86%27.48% 41.30% 62.06% 55.77% 3 mg/kg, i.p., QD *21 days SMSM-151 22.49%28.98% 48.28% 49.06% 58.41% 50.32% 10 mg/kg, p.o., BID *21 days

Example 22: Pharmacodynamics

A-673 cell viability (IC₅₀), splicing (IC₅₀) and brain AUC/Plasma AUC ofSMSMs were determined. As shown in the tables below SMSMs had high CNSexposure.

A-673 cell viability Splicing Compound (IC₅₀) (IC₅₀) Brain/Plasma AUCSMSM-151 ≤5 nM <1 nM 1.4 (PO, rat) SMSM-160 ≤5 nM <1 nM 0 SMSM-167 <0.5nM   <1 nM 0.5 (PO, rat); 0.27 (PO, mouse SMSM-168 ≤5 nM <1 nM 3.7 (PO,rat); 0.46 (PO, mouse) SMSM-169 ≤5 nM <1 nM 0.6 (PO, rat); 0.17 (PO,mouse SMSM-191 <1 nM 0.43 (IP, mouse) SMSM-193 <3 nM SMSM-306 <3 nMSMSM-259 <1 nM 0.05 (IP, mouse) SMSM-245  30 SMSM-251 150 SMSM-257 121SMSM-258 149 SMSM-182 0.1 (IP, mouse) SMSM-187 0.1 (IP, mouse) SMSM-2650.08 (IP, mouse) SMSM-205 0.34 (IP, mouse)

Example 23: Efficacy of SMSMs in Subcutaneous U87-Luc Brain Tumor Modelin Combination with Radiotherapy

Study Aim

To evaluate efficacy of SMSMs in Subcutaneous U87-Luc Brain Tumor Modelin combination with radiotherapy

Experimental Design

Subcutaneous U87-Luc Brain Tumor Model in NcrNude Mice: tumorinoculation on Day 0; compound treatment initiation at 100 mm³ (Day 0),twice daily by oral gavage; radiotherapy treatment on Day 3. Theradiotherapy treatment (10 Gy) was conducted using Image Guided SmallAnimal Radiation Research Platform (SARRP) irradiator (Xstrahl Limited,GU15 3YL).

Experimental Groups

The experimental groups used in this study are shown in the table below.Results are shown in FIGS. 24A and 24B.

# Treatment 1 Treatment 2 Group Mice Treatment 1 Schedule Treatment 2Schedule Group 1 5 None NA Vehicle BID from Day 0 for the duration ofthe study Group 2 5 None NA SMSM-167, 5 mg/kg BID from Day 0 for theduration of the study Group 3 5 10 Gy Day 3 Vehicle BID from Day 0 forthe duration of the study Group 4 5 10 Gy Day 3 SMSM-167, 5 mg/kg BIDfrom Day 0 for the duration of the study

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

wherein,

 is

ring Q is 5-6 or 6-5 fused bicyclic heteroaryl, wherein ring Q is optionally substituted with one or more substituents selected from: halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄ alkyl), —C(═O)N(C₁-C₄ alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄ alkyl), —S(═O)₂N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ fluoroalkyl, C₁-C₄ heteroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —SC₁-C₄ alkyl, —S(═O)C₁-C₄ alkyl, —S(═O)₂(C₁-C₄ alkyl), —NH(cyclopropyl), —OCH₃, —OCF₃, and oxo; X is —NR³— each R1 is independently H, D, C₁-C₆ alkyl, —CD₃, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₃-C₈ cycloalkyl, or C₂-C₇ heterocycloalkyl; R³ is —OR′, —N(R¹)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₃-C₈ cycloalkyl, or C₂-C₇ heterocycloalkyl; Z is CR⁷; and R⁷ is H; W is C₁-C₄ alkylene; R is H; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independently selected from the group consisting of H, F, OR¹, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, and C₁-C₆ heteroalkyl, wherein the alkyl, fluoroalkyl, or heteroalkyl is optionally substituted with hydroxy, amino, methoxy, mono-C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino; a and b are each 0; c and d are each 1; and wherein the compound of Formula (IV) has a stereochemical purity of at least 80%.
 2. The compound of claim 1, wherein R³ is —CH₃.
 3. The compound of claim 1, wherein R³ is C₃-C₈ cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
 4. The compound of claim 1, wherein R³ is —CH₃, —CD₃, —CF₃, —OCH₃, —OCD₃, —OCH₂CH₃, —OCH₂CH₂OH, or —OCH₂CH₂OCH₃.
 5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein W is —CH₂CH₂—.
 6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein

is

R is H; R¹⁵ and R¹⁸ are H; and p is 2 or
 3. 7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein

is

R is H; R¹⁵ and R¹⁸ are CH₃; and p is 2 or
 3. 8. A pharmaceutical composition that comprises the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
 9. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each H.
 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is optionally substituted 5-6 or 6-5 fused bicyclic heteroaryl having 8 to 10 ring atoms, and 1, 2, or 3 ring heteroatoms independently selected from N, O or S.
 11. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is selected from the group consisting of:

wherein each R is independently selected from cyano, halogen, hydroxy, C₁-C₄ alkyl, —OCH₃, —OCD₃, C₁-C₄ alkoxy, and C₃₋₆ cycloalkyl; and m is 0, 1, 2, or
 3. 12. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is

wherein each RB is independently selected from cyano, halogen, hydroxy, C₁-C₄ alkyl, —OCH₃, —OCD₃, C₁-C₄ alkoxy, and C₃₋₆ cycloalkyl; and m is 0, 1, 2, or
 3. 13. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is

and each R⁶ is independently H or C₁-C₄ alkyl.
 14. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein p is
 2. 15. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein p is
 3. 16. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein p is
 2. 17. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein p is
 3. 